Compositions and treatment methods-4

ABSTRACT

The invention relates to the use of compounds to ameliorate or treat an condition such as a cystic fibrosis, neutropenia or other exemplified conditions. Exemplary compounds that can be used include 3β-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene, 1α,3β-dihydroxy-4α-fluoroandrost-5-ene-17-one, 1α,3β,17β-trihydroxy-4α-fluoroandrost-5-ene, 1β,3β-dihydroxy-6α-bromoandrost-5-ene, 1α-fluoro-3β,12α-dihydroxyandrost-5-ene-17-one, 1α-fluoro-3β,4α-dihydroxyandrost-5-ene and 4α-fluoro-3β,6α,17β-trihydroxyandrostane.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of pending U.S. applicationSer. No. 11/549,875, filed Oct. 16, 2003, which is a continuation ofU.S. application Ser. No. 10/651,515, now abandoned, filed Aug. 28,2003, which claims priority of abandoned U.S. provisional applicationSer. No. 60/407,146, filed Aug. 28, 2002, U.S. abandoned provisionalapplication Ser. No. 60/408,332, filed Sep. 4, 2002 and abandoned U.S.provisional application Ser. No. 60/479,257, filed Jun. 17, 2003 all ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to methods to use compounds, such as3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-17β-aminoandrost-5-ene,1α,3β-dihydroxy-4α-fluoroandrost-5-ene,1α,3β,17β-trihydroxy-4α-fluoroandrost-5-ene,1β,3β-dihydroxy-6-bromoandrost-5-ene-17-one,1α-fluoro-3β,12α-dihydroxyandrost-5-ene-17-one,1α-fluoro-3β,4α-dihydroxyandrost-5-ene and4α-fluoro-3β,6α,17β-trihydroxyandrostane to treat, ameliorate or preventneutropenia, cystic fibrosis conditions or other pathological or diseaseconditions or their symptoms.

BACKGROUND

Immune dysregulation can be a component of many pathological diseases orconditions. Such dysregulation may be a factor that favors theestablishment, maintenance or progression of these diseases orconditions. Deficient immune responses or immune suppression can enhancea mammal's susceptibility to infection or to the development of cancer.Conversely, excessive or inappropriate immune responses can play a rolein the establishment or progression of unwanted inflammation orautoimmune conditions. It would thus be advantageous to utilize agentsthat can modulate immune responses and to at least partially reverseimmune dysregulation when such dysregulation is a component of a givenpathological condition. Some agents are known that can ameliorate someaspects of immune dysregulation, but typically such agents have theirown unwanted effects on either the host's immune system or other organsor tissues. Agents such as glucocorticoid steroids have been used toreduce unwanted inflammation in a number of clinical conditions, butsuch compounds often have serious limitations, such as inducing immunesuppression or causing unwanted mood changes.

Human and mammalian immune responses to infections or other conditionsare often characterized by responses mediated by different immuneeffector cell populations. In some situations, helper T cells designatedTh1 in the murine system, facilitate immune effector functions that aretypically dominated by cell-mediated responses. In other cases, helper Tcells designated Th2 cells facilitate immune effector functions that aretypically dominated by humoral responses. A vigorous Th1 response isusually desirable to help clear infections or to slow the progression ofan infection. When a subject's immune response is biased to, ordominated by, a Th2-type response, the cytokines associated with the Th2response tend to suppress the immune system's capacity to mount avigorous Th1 response at the same time. The converse is also generallytrue. When mammalian immune responses begin to result in an increasingTh1 response, Th2 responses tend to weaken. Insufficient Th1 responsesmay be associated with progression of some infections or otherconditions, see, e.g., M. Clerici and G. M. Shearer, Immunol. Today14:107-111, 1993; M. Clerici and G. M. Shearer, Immunol. Today15:575-581, 1994.

There is a current need for cost-effective pharmaceutical agents andtreatment methods for treating various immune dysregulation conditions.The invention provides compounds that can be used in such treatments totreat or ameliorate one or more aspects of immune dysregulationconditions. Such agents can be used to treat autoimmune or inflammationconditions, immune suppression conditions, infections, blood celldeficiencies and other described conditions. The agents and methods areuseful to ameliorate these conditions or one or more symptoms associatedwith any of these conditions. The use of these agents can be combinedwith one or more conventional treatments for these disorders.

DESCRIPTION OF THE INVENTION

Summary of invention embodiments. In principal embodiments the inventionprovides therapeutic treatment methods.

The methods include a method to prevent, treat, ameliorate or slow theprogression of cystic fibrosis, sickle cell disease, neutropenia orthrombocytpoenia in a subject, or to treat a symptom of the cysticfibrosis, sickle cell disease, neutropenia or thrombocytopenia,comprising administering to a subject, or delivering to the subject'stissues, an effective amount of a formula 1 compound having thestructure 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14

or a metabolic precursor or a metabolite thereof, wherein

R¹⁰ moieties at the 5 (if present), 8, 9 and 14 positions respectivelyare in the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β,α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β,β,β,β,α or β,β,β,β configurations,

wherein R^(10A), R^(10B), R^(10C), R^(10D) and R^(10E) respectively arein the α,α, α,β, β,α or β,β configurations,

wherein, each R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) independently are —H, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, an ester, a thioester, a thionoester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate, a carbamate, ahalogen, an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety, an optionally substituted heteroarylmoiety, an optionally substituted heterocycle, an optionally substitutedmonosaccharide, an optionally substituted oligosaccharide, a nucleoside,a nucleotide, an oligonucleotide, a polymer, or,

one more of R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) are ═O, ═S, ═N—OH, ═CH₂, ═CH—CH₃, or anindependently selected spiro ring and the hydrogen atom or the secondvariable group that is bonded to the same carbon atom is absent, or,

one or more of two adjacent R¹-R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) comprise an independently selected epoxide, acetal,a thioacetal, ketal or thioketal;

R⁷ is —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—C(R¹⁰)₂—,—C(R¹⁰)₂—O—C(R¹⁰)₂—, —C(R¹⁰)₂—S—C(R¹⁰)₂—, —C(R¹⁰)₂—NR^(PR)—C(R¹⁰)₂—,—O—, —O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—;

R⁸ and R⁹ independently are —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —O—,—O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—, or one orboth of R⁸ or R⁹ independently are absent, leaving a 5-membered ring;

R¹³ independently is C₁₋₆ alkyl; and

R^(PR) independently is —H or a protecting group. In typicalembodiments, one or two of R^(10A), R^(10B), R^(10C), R^(10D) andR^(10E) are not hydrogen or one R⁴ is —NH₂, an optionally substitutedamine, —N(R^(PR))², ═NOH, ═NO-optionally substituted alkyl, an amide oran N-linked amino acid.

Other embodiments include (1) certain new formula 1 compounds, which arenew chemical entities, (2) compositions that comprise a formula 1compound and another compound or an excipient, (3) formulations thatcomprise a formula 1 compound and 1, 2, 3, 4, 5, 6 or more excipients.The formulations can be designed for human pharmaceutical use or theycan be suitable for veterinary use. Therapeutic use embodiments include(1) use of a formula 1 compound for the preparation of a medicament and(2) use of a formula 1 compound for the preparation of a medicament forthe prophylaxis or treatment of a condition or symptom disclosed herein.

Other embodiments are as described elsewhere in the specificationincluding the claims.

Definitions. As used herein and unless otherwise stated or implied bycontext, terms that are used herein have the meanings defined below.Unless otherwise contraindicated or implied, e.g., by including mutuallyexclusive elements or options, in these definitions and throughout thisspecification, the terms “a” and “an” mean one or more and the term “or”means and/or.

Reference to an androstane compound, e.g.,3β,16α,17β-trihydroxyandrostane, means that the hydrogen atom at the5-position is in the α-configuration. For androstanes with hydrogen inthe β-configuration, the compound name will specify this configuration,e.g., 3β,16α,17β-trihydroxy-5β-androstane.

An “invention formulation”, “formulation”, “pharmaceutical formulation”or the like means a composition that one can administer to a subject,e.g., human, mammal or other animal, without further manipulations thatchange the ingredients or the ingredient proportions that are present.Formulations will typically comprise a single formula 1 compound and oneor more excipients. Formulations are suitable for human or veterinaryapplications and would typically have expected characteristics for theformulation, e.g., parenteral formulations for human use would usuallybe sterile and stored in a suitable closed container.

When referring to mixtures that contain a formula 1 compound, an“invention composition”, “composition” or the like means a composition,that is a formulation or that can be an intermediate one can use, e.g.,to make a formulation or a formula 1 compound. Compositions also includeother types of mixtures, e.g., (1) reagents for assays or cells that areoptionally contacted with a formula 1 compound or mixtures of compoundsand (2) compounds used to make a formula 1 compound or by-products offormula 1 compound synthesis or analysis. Invention compositions includecompositions where further processing may be required before it is aformulation, e.g., mixing or addition of a desired amount of anexcipient.

Phrases such as “administration of a compound of formula 1”, “treatmentwith a formula 1 compound”, “use of a formula 1 compound” or similarterms mean that the compound(s) is administered to, contacted with ordelivered to, the subject or to the subject's cells or tissues in vitroor in vivo by one or more suitable methods, e.g., in vivo delivery canbe by an oral, topical, subcutaneous, parenteral, buccal or sublingualroute.

Expressions such as “a formula 1 compound(s)”, “a formula 1 compound”and the like mean invention compositions or formulations where one ormore than one formula 1 compound is present, e.g., in a composition, oris used in the disclosed method, typically 1, 2, 3 or 4, usually 1. Anyreference to a “formula 1 compound”, “one or more compounds of formula1” or the like means that the formula 1 compound can have the formula 2structure or any other structure disclosed herein that is within thedefinition of formula 1 compounds. The phrase formula 1 compound orformula 1 compound(s) is sometimes abbreviated as “F1C” or “F1C(s)” andformula 1 compounds may be abbreviated as “F1Cs”.

Reference to subject matter “as disclosed herein” such as a “therapeutictreatment or agent as disclosed herein”, a “dosing protocol as disclosedherein” or a “clinical condition or symptom as disclosed herein” or thelike means a treatment, agent, protocol, condition, symptom or the likethat is described herein or in any reference that is cited herein.

An “excipient”, “carrier”, “pharmaceutically acceptable excipient”,“pharmaceutically acceptable carrier” or similar terms mean one or morecomponent(s) or ingredient(s) that is acceptable in the sense of beingcompatible with the other ingredients of invention compositions orformulations and not overly deleterious to the patient, animal, tissuesor cells to which the F1C, composition or formulation is to beadministered.

A “subject” means a human or animal. Usually the animal is a mammal orvertebrate such as a primate, rodent, lagomorph, domestic animal or gameanimal. Primates include chimpanzees, cynomologous monkeys, spidermonkeys, and macaques, e.g., Rhesus or Pan. Rodents and lagomorphsinclude mice, rats, woodchucks, ferrets, rabbits and hamsters.

The terms “effective amount”, “effective dose” or the like withreference to a F1C(s) mean an amount of the F1C(s) that is sufficient toelicit a desired response, e.g., detectable restoration of normal immuneresponsiveness in an immunodeficient subject to which it isadministered, e.g., a human, or to detectable modulation or ameliorationof an immune or cellular parameter or a clinical condition or symptom.An effective amount, e.g., for human therapeutic use, may be a singledose or two or more subdoses of a F1C administered in one day, or it maybe administered as multiple doses over a period of time, e.g., over 1,2, 3, 4 or about 7 days to about 1 year.

Terms such as “use”, “treat”, “treatment”, “address” or the like in thecontext of using the F1Cs in the treatment methods or other methodsdisclosed herein mean that a F1C is administered to a subject, deliveredto the subject's tissues or contacted with tissues, cells or cell freesystems in vivo or in vitro, e.g., as described herein or a referencecited herein. Typically such use or treatment results in, e.g., (1)detectable improvement in or amelioration of the condition or symptombeing treated, (2) detectable modulation in the activity, level ornumbers of a relevant biomolecule, therapeutic immune cell population ora pathological cell population, (3) slowing of the progression of acondition or delaying its onset, or reduction of the severity of asymptom(s) of the condition or (4) another detectable response asdescribed herein.

Thus, a F1C use or treatment typically results in detectable modulationin a relevant immune parameter such as modulation of the level, activityor relative amount of a target effector or suppressor immune cellpopulation, interleukin, cytokine, chemokine, immunoglobulin compared toa suitable control, e.g., untreated. A F1C treatment can also causemodulation of the level or activity of a relevant transcription factor,enzyme, cell biological activity or level or activity of the etiologicalagent of the disease such as a pathogen, tumor cell or autoreactiveimmune cell subset. A treatment with a F1C may be used to delay orprevent the onset of a disease, symptom or complication or to ameliorateor slow the progression of a preexisting disease, condition, symptom orcomplication, or to facilitate elimination of a disease, condition,symptom or complication.

“Alkyl” as used here means linked normal, secondary, tertiary or cycliccarbon atoms, i.e., linear, branched, cyclic or any combination thereof.Alkyl moieties, as used herein, may be saturated, or unsaturated, i.e.,the moiety may comprise one, two, three or more independently selecteddouble bonds or triple bonds. Unsaturated alkyl moieties includemoieties as described for alkenyl and alkynyl moieties described below.The number of carbon atoms in an alkyl group or moiety can vary andtypically is 1 to about 50, e.g., about 1-30 or about 1-20, unlessotherwise specified, e.g., C₁₋₈ alkyl or C1-C8 alkyl means an alkylmoiety containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. When an alkylgroup is specified, species may include methyl, ethyl, 1-propyl(n-propyl), 2-propyl (1-propyl, —CH(CH₃)₂), 1-butyl (n-butyl),2-methyl-1-propyl (i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl, 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)₂), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), cyclopropyl(—CH<CH₂CH₂), cyclobutyl (—CH<CH₂CH₂CH₂), cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, —(CH₂)_(n)—(CHCH₃)_(m)—(CH₂)_(o)—CH₃,—(CH₂)_(n)—(CHC₂H₅)_(m)—(CH₂)_(o)—CH₃ and species and groups describedbelow for alkenyl, alkynyl groups aryl groups, arylalkyl groupsalkylaryl groups and the like, where n, m and o independently are 0, 1,2, 3, 4, 5, 6, 7 or 8.

For any group or moiety described by a given range of carbon atoms, thedesignated range means that any individual number of carbon atoms isdescribed. Thus, reference to, e.g., “C1-C4 optionally substitutedalkyl”, “C₂₋₆ alkenyl”, or “C2-C6 optionally substituted alkenyl”,specifically means that a 1, 2, 3 or 4 carbon optionally substitutedalkyl moiety as defined herein is present, or a 2, 3, 4, 5 or 6 carbonalkenyl or optionally substituted alkenyl moiety as defined herein ispresent. All such designations are expressly intended to disclose all ofthe individual carbon atom groups and thus “C1-C4 optionally substitutedalkyl” means, e.g., 3 carbon alkyl, 4 carbon substituted alkyl and thelike are disclosed and can be expressly referred to or named.

“Alkenyl” as used here means a moiety that comprises linked normal,secondary, tertiary or cyclic carbon atoms, i.e., linear, branched,cyclic or any combination thereof, that comprises one or more doublebonds (e.g., —CH═CH—), e.g., 1, 2, 3, 4, 5, 6 or more, typically 1 or 2.The number of carbon atoms in an alkenyl group or moiety can vary andtypically is 2 to about 50, e.g., about 2-30 or about 2-20, unlessotherwise specified, e.g., C₂₋₈ alkenyl or C₂₋₈ alkenyl means an alkenylmoiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms. When an alkenylgroup is specified, species may include methylene (═CH₂),methylmethylene (═CH—CH₃), ethylmethylene (═CH—CH₂—CH₃),═CH—CH₂—CH₂—CH₃, vinyl (—CH═CH₂), allyl,—(CH₂)_(n)—(CH═CH)—(CH₂)_(m)—CH₃, —(CH₂)_(n)—(CCH₃═CH)—(CH₂)_(m)—CH₃,—(CH₂)_(n)—(CH═CCH₃)₃—(CH₂)_(m)—CH₃ and—(CH₂)_(n)—(CH═CH)₀₋₁—(CH₂)_(m)—CH₂CH═CH₂, where n and m independentlyare 0, 1, 2, 3, 4, 5, 6, 7 or 8.

“Alkynyl” as used here means a moiety that comprises linked normal,secondary, tertiary or cyclic carbon atoms, i.e., linear, branched,cyclic or any combination thereof, that comprises one or more triplebonds (—C═C—), e.g., 1, 2, 3, 4, 5, 6 or more, typically 1 or 2 triplebonds, optionally comprising 1, 2, 3, 4, 5, 6 or more double bonds, withthe remaining bonds being single bonds. The number of carbon atoms in analkenyl group or moiety can vary and typically is 2 to about 50, e.g.,about 2-30 or about 2-20, unless otherwise specified, e.g., C₂₋₈ alkynylor C2-8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or 8carbon atoms. When an alkynyl group is specified, groups and species mayinclude —CCH, —CCCH₃, —CCCH₂CH₃, —CCC₃H₇, —CCCH₂C₃H₇,—(CH₂)_(n)—(C≡C)—(CH₂)_(m)—CH₃, and—(CH₂)_(n)—(C≡C)₀₋₁—(CH₂)_(m)—CH₂C≡CH, where n and m independently are0, 1, 2, 3, 4, 5, 6, 7 or 8.

“Aryl” means an aromatic ring or fused ring system with no ringheteroatoms, e.g., phenyl or naphthyl.

“Arylalkyl” means a moiety where an alkyl group is bonded to an arylgroup, i.e., -alkyl-aryl, where alkyl and aryl groups are as describedabove, e.g., —CH₂—C₆H₅ or —CH₂CH(CH₃)—C₆H₅.

“Alkylaryl” means a moiety where an aryl group is bonded to an alkylgroup, i.e., -aryl-alkyl, where aryl and alkyl groups are as describedabove, e.g., —C₆H₄—CH₃ or —C₆H₄—CH₂CH(CH₃).

“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”,substituted alkylaryl”, “substituted arylalkyl”, “substitutedheterocycle”, “substituted aryl”, “substituted monosaccharide” and thelike mean an alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle,aryl, monosaccharide or other group or moiety as defined or disclosedherein that has a substituent(s) that replaces a hydrogen atom(s) or asubstituent(s) that interrupts a carbon atom chain. Substitutedheterocycles may thus have a substituent bonded to a ring carbon or aring heteroatom such as a nitrogen.

Substituents are independently chosen when more than one is present.Alkenyl and alkynyl groups that comprise a substituent(s), areoptionally substituted at a carbon that is one or more methylene moietyremoved from the double bond, e.g., the substituent is optionallyseparated by one, two, three or more independently selected —CH₂—,—CH(C₁₋₆ optionally substituted alkyl)-, —CH(C₁₋₆ optionally substitutedalkenyl)-, —CH(C₁₋₆ optionally substituted alkynyl)-, —CH(optionallysubstituted heterocycle)-, —CH(optionally substituted aryl-optionallysubstituted alkyl)- or —CH(optionally substituted alkyl-optionallysubstituted aryl)-moieties.

“Heterocycle” or “heterocyclic” includes by way of example and notlimitation the heterocycles described in Paquette, Leo A.; “Principlesof Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. 1960, 82:5566. Heterocycles are typically bondedto the steroid nucleus through a carbon, nitrogen or sulfur atom in theheterocycle ring.

Examples of heterocycles include by way of example and not limitationpyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinoyl.

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Typically, nitrogen bonded heterocyclesinclude 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl,and 1-piperidinyl.

“Heteroaryl” means an aromatic ring or two or more fused rings thatcontain one or more aromatic rings where the ring or fused ringscomprise 1, 2, 3 or more heteroatoms, usually oxygen (—O—), nitrogen(—NX—) or sulfur (—S—) where X is —H, a protecting group or C₁₋₆optionally substituted alkyl, usually —H. Examples are as described forheterocycle.

“Alcohol” as used herein means an alcohol that comprises a C₁₋₁₂ alkylmoiety substituted at a hydrogen atom with one hydroxyl group. Alcoholsinclude methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol,s-butanol, t-butanol, n-pentanol, i-pentanol, n-hexanol, cyclohexanol,n-heptanol, n-octanol, n-nonanol and n-decanol. The carbon atoms inalcohols can be straight, branched or cyclic. Alcohol includes anysubset of the foregoing, e.g., C₁₋₄ alcohols (alcohols having 1, 2, 3 or4 carbon atoms).

“Halogen” means fluorine, chlorine, bromine or iodine.

“Protecting group” means a moiety that prevents or reduces the atom orfunctional group to which it is linked from participating in unwantedreactions. For example, for —OR^(PR), R^(PR) may be hydrogen or aprotecting group for the oxygen atom found in a hydroxyl, while for—C(O)—OR^(PR), R^(PR) may be hydrogen or a carboxyl protecting group,for —SR^(PR), R^(PR) may be hydrogen or a protecting group for sulfur inthiols for instance, and for —NHR^(PR) or —N(R^(PR))₂—, R^(PR) may behydrogen or a nitrogen atom protecting group for primary or secondaryamines. Hydroxyl, amine, ketones and other reactive groups are found inF1Cs at, e.g., R¹ or R². These groups may require protection againstreactions taking place elsewhere in the molecule. The protecting groupsfor oxygen, sulfur or nitrogen atoms are usually used to preventunwanted reactions with electrophilic compounds, such as acylatingagents used, e.g., in steroid chemistry.

“Ester” means a moiety that contains a —C(O)—O— structure. Typically,esters as used here comprise an organic moiety containing about 1-50carbon atoms (e.g., about 2-20 carbon atoms) and 0 to about 10independently selected heteroatoms (e.g., O, S, N, P, Si), where theorganic moiety is bonded to a formula 1 steroid nucleus at, e.g., R¹ orR² through the —C(O)—O— structure, e.g., organic moiety-C(O)—O-steroidor organic moiety-O—C(O)-steroid. The organic moiety usually comprisesone or more of any of the organic groups described herein, e.g., C₁₋₂₀alkyl moieties, C₂₋₂₀ alkenyl moieties, C₂₋₂₀ alkynyl moieties, arylmoieties, C₂₋₉ heterocycles or substituted derivatives of any of these,e.g., comprising 1, 2, 3, 4 or more substituents, where each substituentis independently chosen. Exemplary substitutions for hydrogen or carbonatoms in these organic groups are as described above for substitutedalkyl and other substituted moieties. Substitutions are independentlychosen. The organic moiety includes compounds defined by the R₄variable. The organic moieties exclude obviously unstable moieties,e.g., —O—O—, except where such unstable moieties are transient speciesthat one can use to make a compound with sufficient chemical stabilityfor one or more of the uses described herein, including for synthesis ofthe formula 1 or other compounds. The substitutions listed above aretypically substituents that one can use to replace one or more carbonatoms, e.g., —O— or —C(O)—, or one or more hydrogen atom, e.g., halogen,—NH₂ or —OH. Exemplary esters include one or more independently selectedacetate, enanthate, propionate, isopropionate, isobutyrate, butyrate,valerate, caproate, isocaproate, hexanoate, heptanoate, octanoate,nonanoate, decanoate, undecanoate, phenylacetate or benzoate, which aretypically hydroxyl esters.

“Acetal”, “thioacetal”, “ketal”, “thioketal” “spiro ring” and the likemean a cyclic organic moiety that is bonded to a steroid ring atom inthe F1Cs, e.g., steroid nucleus atoms at one, two or more of the 1, 2,3, 4, 6, 7, 11, 12, 15, 16, 17, 18 or 19 positions. Typically, acetalscomprise an organic moiety containing about 1-20 carbon atoms (e.g.,about 1-10 carbon atoms) and 0 to about 10 independently selectedheteroatoms (e.g., O, S, N, P, Si). For acetals (or ketals), the steroidnucleus atoms are usually carbons and the acetal is bonded to a steroidcarbon through two oxygen atoms. Thioacetals (or thioketals) are bondedto the steroid nucleus through one oxygen and one sulfur atom or, moreoften, through two sulfur atoms. One, two or more of e.g., R¹, R², R³,R⁴, R¹⁰ at the 2, 11 or 15 positions, R^(10A), R^(10B), R^(10C) andR^(10D), may be an independently selected acetal, thioacetal or spiroring in any of the F1Cs disclosed herein. The oxygen or sulfur atoms inketals and thioketals are linked by an optionally substituted alkylmoiety. Typically the alkyl moiety is an optionally substituted C1-C6alkylene or branched alkyl structure such as —C(CH₃)₂—, —CH(CH₃)—,—CH₂—, —CH₂—CH₂—, —C[(C2-C4 alkyl)₂]_(1,2,3)- or —[CH(C2-C4alkyl)]_(1,2,3)-. Acetals include moieties having the structure—O—[C(R³⁶)₂]₁₋₆—O—, —O—CH₂—[C(R³⁶)₂]₂—O—, —O—CH₂—CH₂—[C(R³⁶)₂]₂—O—,—O—CH₂—[C(R³⁶)₂]₂—CH₂—O—, and —O—CH₂—C(R³⁶)₂—O—, where each R³⁶independently is —H, —OH, ═O, ═S, —SH, —F, —Cl, —Br, —I or an organicmoiety such as C1-C6 alkyl (e.g., methyl, ethyl, hydroxymethyl orhalomethyl), C2-C6 alkenyl, C2-C6 alkenyl, aryl or an heterocycle, anyof which are optionally substituted, e.g., —CF₃ or —CH₂OH. In some ofthese embodiments, one R³⁶ is —H and the other is another atom ormoiety, e.g., —OH, methyl or a halogen. In other embodiments, neitherR³⁶ is —H, e.g., both are methyl. Thioacetals include moieties thatcomprise a —S—[C(R³⁶)₂]₁₋₆—O— or —S—[C(R³⁶)₂]₁₋₆—S— structure where theopen valences are bonded to the same carbon on the steroid nucleus.Other exemplary acetal and thioacetals are —O—C(CH₃)₂—O—,—O—CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—O—, —O—CH₂—O—, —O—C(CH₃)(heterocycle)-O—,—O—CH(heterocycle)-O—, —O—C(CH₃)(aryl)-O—, —O—CH(aryl)-O—,—S—C(CH₃)₂—O—, —S—C(CH₃)₂—S—, —S—CH₂—CH₂—O—, —S—CH₂—CH₂—S—, —S—CH₂—O—,—S—CH₂—S—, —O—C(CH₃)₂—CH₂—O—, —O—C(CH₃)₂—C(CH₃)₂—O—, —S—C(CH₃)₂—CH₂—O—and —O—C(CH₃)₂—CH₂—S—. Some of these moieties can serve as protectinggroups for a ketone or hydroxyl, e.g., acetals such as —O—CH₂—CH₂—CH₂—O—or —O—CH₂—CH₂—O— for ketones, which form a spiro ring that can beremoved by chemical synthesis methods or by metabolism in cells orbiological fluids. For any spiro ring disclosed herein and unlessotherwise specified, the 1^(st) and 2^(nd) open valences can be bondedto the carbon in the steroid nucleus in the α- and β-configurationsrespectively or in the α- and β-configurations respectively. Forexample, in a spiro —NH—CH₂—CH₂—O— structure, the 1^(st) open valence,i.e., at the nitrogen atom, can be, e.g., at the 17-position in theβ-configuration and the 2^(nd) open valence, i.e., at the oxygen, wouldthen be in the α-configuration.

“Amide”, “amide derivative” and the like mean an organic moiety asdescribed for ester that comprises a —C(O)—NR^(PR)— or —C(O)—NH— moiety,where R^(PR) is —H or a protecting group. In some embodiments, the—C(O)NR^(PR)— group is linked to the steroid nucleus at a variable groupsuch as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸, i.e., organicmoiety-C(O)NR^(PR)-steroid, organic moiety-C(O)—NH-steroid orsteroid-C(O)NR^(PR)-organic moiety. The organic moiety is as describedabove for esters.

“Ether” means an organic moiety as described for ester that comprises 1,2, 3, 4 or more —O— moieties, usually 1 or 2. In some embodiments, the—O— group is linked to the steroid nucleus at a variable group such asR¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸, e.g., organic moiety-O-steroid. The organicmoiety is as described above for esters.

“Acyl group” or “acyl” means an organic moiety as described for esterthat comprises 1, 2, 3, 4 or more —C(O)— groups. In some embodiments,the —C(O)— group is linked to the steroid nucleus at a variable groupsuch as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸, e.g., organic moiety-C(O)-steroid.The organic moiety is as described above for esters.

“Carbonate” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O—C(O)—O— structures. Typically, carbonategroups as used here comprise an organic moiety containing about 1-50carbon atoms and 0 to about 10 independently selected heteroatoms (e.g.,O, S, N, P, Si) linked to a formula 1 steroid nucleus at a variablegroup such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —O—C(O)—O—structure, e.g., organic moiety-O—C(O)—O-steroid. The organic moiety isas described above for esters.

“Carbamate” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O—C(O)NR^(PR)— structures where R^(PR) is—H, a protecting group or an organic moiety as described for ester.Typically, carbamate groups as used here comprise an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 independentlyselected heteroatoms (e.g., O, S, N, P, Si) linked to a formula 1steroid nucleus at a variable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸through the —O—C(O)—NR^(PR)— structure, e.g., organicmoiety-O—C(O)—NR^(PR)-steroid or steroid-O—C(O)—NR^(PR)-organic moiety.The organic moiety is as described above for esters.

Optionally substituted alkyl group, optionally substituted alkenylgroup, optionally substituted alkynyl group, optionally substituted arylmoiety and optionally substituted heterocycle mean an alkyl, alkenyl,alkynyl, aryl or heterocycle moiety that contains an optionalsubstitution(s). Such moieties include C₁₋₂₀ alkyl moieties, C₂₋₂₀alkenyl moieties, C₂₋₂₀ alkynyl moieties, aryl moieties, C₂₋₉heterocycles or substituted derivatives of any of these.

As used herein, position numbers that are given for the F1Cs use thenumbering convention for cholesterol.

As used herein, “innate immunity” refers to one or more componentstypically associated with nonspecific immune defense mechanisms in asubject. These components include the alternate complement pathway,e.g., Factor B, Factor D and properdin; NK cells, phagocytes (monocytes,macrophages), neutrophils, eosinophils, dendritic cells, fibrocytes;anti-microbial chemicals, e.g., one or more of defensins; physicalbarriers—skin, mucosal epithelium; or certain interleukins, chemokines,cytokines, lung or alveolar macrophage respiratory burst activity or alung surfactant protein such as surfactant protein A or surfactantprotein D. Innate immunity plays a role in resistance to intracellularparasite infections, e.g., white blood cell infection, a liverinfection, and other infections, e.g., lymph node infections. Detectableenhancement of innate immunity mechanism by F1Cs or method describedherein can also enhance phagolysosome fusion or movement, which somepathogens, e.g., intracellular bacteria such as mycobacteria, orListeria inhibit.

Terms such as “immune dysregulation”, “immune dysregulation condition”,“unwanted immune response” and the like mean that a subject has or issubject to developing an immune response that is not desirable or issuboptimal for the subject's condition. Such dysregulation or unwantedresponses can arise from various clinical conditions or diseases or as aresult of treatment of such conditions or diseases, e.g., inflammation,autoimmunity, organ or tissue transplant rejection (e.g., allograft,xenograft), infections, cancers, chemotherapy treatments, trauma,allergy conditions or in conditions where a subject mounts a Th1, Tc1,Th2 or Tc2 immune response that is considered to be pathogenic,ineffective, insufficient or suboptimal. Immune dysregulation conditionsare as described herein or in the cited references.

Terms such as “cellular response”, “cellular activity”, “biologicalresponse”, “biological activity” and the like mean a response oractivity that is detectably modulated in response to the presence of aF1C. Such responses or activities can be direct effects or indirecteffects on one or more cellular activities or on the expression or levelof one or more molecules that the affected cell(s) bind, sequester,synthesize or respond to. Such responses or activities include adetectable change in the synthesis or level of one or more cytokines,growth factors, transcription factors (including receptors and theircofactors), enzymes, Th1- or Th2-associated antibody subtype responsesor the like. Typically, the cytokines, growth factors, transcriptionfactors, enzymes or antibodies that are modulated are involved in theamelioration of a pathological condition or in the establishment,maintenance, severity or progression of a pathological condition.

As used herein, references to CD molecules, specific immune cellsubsets, immune responses and the like, generally use nomenclature thatapplies to molecules, cells or the like that are found in humans.Analogs or counterparts of such molecules, cells or the like in otherspecies may have a differing nomenclature, but are included in thisinvention. A description of the nomenclature and function of various CDmolecules and immune cell subsets are as found in the scientificliterature. References to Th0, Th1 or Th2 cells and references to Th1 orTh2 immune responses in the context of human patients refers to thehuman counterparts of the murine Th0, Th1 or Th2 immune cells orresponses. For reviews see, e.g., A. K. Abbas et al., editors, Cellularand Molecular Immunology, W.B. Saunders Company, third edition, 1997,ISBN 0-7216-4024-9, pages 4-469, and I. Kimber and M. K. Selgrade,editors, T Lymphocyte Subpopulations in Immunotoxicology, John Wiley &Sons Ltd., 1998, ISBN 0-471-97194-4, pages 1-53.

“Immunosuppressive molecule” means molecules such as cyclosporin,cyclohexamide, mitomycin C, adriamycin, taxol and amphotericin B. Thesemolecules tend to have toxicities toward the immune system and aredirectly or indirectly immunosuppressive, e.g., they are toxic todividing cells, they inhibit proliferation of immune cell precursors orthey can downregulate an otherwise desired or improved immune responseor condition.

“Nuclear hormone receptor” means a gene product, typically as a proteinmonomer or dimer that can bind to a ligand and affect transcription ofone or more genes. Ligands include, e.g., certain natural steroids,steroid analogs, F1Cs or another ligand such as a lipid, e.g., aprostaglandin, or the like. Nuclear hormone receptors include orphansteroid receptors, which typically function as heterodimers and theclassical steroid receptors, e.g., androgen receptor (“AR”), estrogenreceptor α (“ERα”), estrogen receptor β (“ERβ”), that function ashomodimers.

Salts of F1Cs. Invention embodiments include salts and complexes ofF1Cs, including pharmaceutically acceptable or salts that are relativelynon-toxic. Some of the F1Cs have one or more moieties that carry atleast a partial positive or negative charge in aqueous solutions,typically at a pH of about 4-10, that can participate in forming a salt,a complex, a composition with partial salt and partial complexproperties or other noncovalent interactions, all of which we refer toas a “salt(s)”. Salts are usually biologically compatible orpharmaceutically acceptable or non-toxic, particularly for mammaliancells. Salts that are biologically toxic are optionally used withsynthetic intermediates of F1Cs. When a water-soluble composition isdesired, monovalent salts are usually used.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts that areoptionally prepared in this way are salts containing Li⁺, Na⁺, and K⁺. Aless soluble metal salt can be precipitated from the solution of a moresoluble salt by adding a suitable metal compound. Invention salts may beformed from acid addition of certain organic acids, such as organiccarboxylic acids, and inorganic acids, such as alkylsulfonic acids orhydrogen halide acids, to acidic or basic centers on F1Cs, such as basiccenters on the invention pyrimidine base analogs. Metal salts includeones containing Na⁺, Li⁺, K⁺, Ca⁺⁺ or Mg⁺⁺.

Salts are produced by standard methods, including dissolving free basein an aqueous, aqueous-alcohol or aqueous-organic solution containingthe selected acid, optionally followed by evaporating the solution. Thefree base is reacted in an organic solution containing the acid, inwhich case the salt usually separates directly or one can concentratethe solution.

Suitable amine salts include amines having sufficient basicity to form astable salt, usually amines of low toxicity including trialkyl amines(tripropylamine, triethylamine, trimethylamine), procaine,dibenzylamine, N-benzyl-betaphenethylamine, ephenamine,N,N′-dibenzylethylenediamine, N-ethylpiperidine, benzylamine anddicyclohexylamine.

Salts include organic sulfonic acid or organic carboxylic acid salts,made for example by addition of the acids to basic centers, typicallyamines. Exemplary sulfonic acids include C₆₋₁₆ aryl sulfonic acids,C₆₋₁₆ heteroaryl sulfonic acids and C₁₋₁₆ alkyl sulfonic acids such asphenyl sulfonic acid, α-naphthalene sulfonic acid, β-naphthalenesulfonic acid, (S)-camphorsulfonic acid, methyl (CH₃SO₃H), ethyl(C₂H₅SO₃H), n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl,pentyl and hexyl sulfonic acids. Exemplary organic carboxylic and otheracids include C₁₋₁₆ alkyl, C₆₋₁₆ aryl carboxylic acids and C₄₋₁₆heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic,malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic,oxalic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic, nicotinic, 2-phenoxybenzoic, methanesulfonic, pamoic,propionic, toluenesulfonic and trifluoroacetic acids.

Invention salts include those made from inorganic acids, e.g., HF, HCl,HBr, HI, H₂SO₄, H₃PO₄, Na₂CO₃, K₂CO₃, CaCO₃, MgCO₃ and NaClO₃. Suitableanions, which are optionally present with a cation such a Ca⁺⁺, Mg⁺⁺,Li⁺, Na⁺ or K⁺, include arsenate, arsenite formate, sorbate, chlorate,perchlorate, periodate, dichromate, glycodeoxycholate, cholate,deoxycholate, desoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, tetraborate, nitrate, nitrite, sulfite, sulfamate,hyposulfite, bisulfite, metabisulfite, thiosulfate, thiocyanate,silicate, metasilicate, CN⁻, gluconate, gulcuronate, hippurate, picrate,hydrosulfite, hexafluorophosphate, hypochlorite, hypochlorate, borate,metaborate, tungstate and urate.

Salts also include the F1C salts with one or more amino acids. Manyamino acids are suitable, especially the naturally-occurring amino acidsfound as protein components, although the amino acid typically is onebearing a side chain with a basic or acidic group, e.g., lysine,arginine, histidine or glutamic acid, or a neutral group such asglycine, serine, threonine, alanine, isoleucine, or leucine.

Embodiments of formula 1 compounds. For formula 1 compounds (“F1Cs”), 2,3 or more of R¹, R², R³ and R⁴ are usually not —H, and typically one orboth R¹ and R⁴, R³ and R⁴, R², R³ and R⁴ or R² and R⁴ are not —H, and/or1 or 2 of R^(10A), R^(10B), R^(10C) and R^(10D) are optionally not —H.For any F1C disclosed herein, steroid nucleus carbon atoms that containtwo variable groups (e.g., two R¹⁰ at R⁸ or R⁹ or two R³ or R⁴ at the16- or 17-position), each variable group is independently selected andeach can thus be the same or different, e.g., both can be methyl, ethyl,methoxy, ethoxy, —F, —Cl, —Br, —I, or they can be different. As isapparent from the F1C structures, a double bond can be present at eitherthe 4-5 position or at the 5-6 position, but not at both positions atthe same time. Steroid nucleus carbon atoms refers generally to thecarbons that make up the rings in F1Cs and carbons, if present, that arebonded to the 10, 13 and 17 positions. Additional carbons that may be atthe 17-position are typically numbered using the cholesterol numberingsystem, although any other suitable nomenclature can be used to describespecies or genera of F1C. Exemplary F1C embodiments are described below.

F1Cs include 16α-bromoepiandrosterone (“BrEA”) hemihydrate

which has previously been described, e.g., WO 00/56757. BrEA hemihydrateis used as a F1C either as a pure compound or substantially free ofother forms of BrEA, such as amorphous BrEA or anhydrous BrEA.

F1Cs include compounds having the structure 5, 6, 7, 8, 9 and 10,

or a metabolic precursor, a metabolite or salt thereof, wherein

each R¹, R², R³, R⁴, R¹⁰ at the 2, 11 and 15 positions, R^(10A),R^(10B), R^(10C) and R^(10D) independently are —H, —OH, —OR^(PR),—SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —ONO₂,—N₃, —NH₂, —COOH, —OSO₃H, —OPO₃H, ═O, ═S, ═NOH, ═CH₂, ═CH₂CH₃,═N—NH—C(═NH)—N(R^(PR))₂, ═N—NH—C(═NH)—NH₂, an ester, a thioester, athionoester, a phosphoester, a phosphothioester, a phosphonoester, aphosphiniester, a sulfite ester, a sulfate ester, a sulfoxide, asulfamate, a sulfonate, a sulfamide, a sulfinamide, a sulfurous diamide,an amide, an amino acid, a peptide, an ether, a thioether, an acylgroup, a thioacyl group, a carbonate, a carbamate, a halogen, an acetal,a thioacetal a spiro ring, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl moiety, an optionally substitutedheteroaryl moiety, an optionally substituted heterocycle, an optionallysubstituted monosaccharide, an optionally substituted oligosaccharide, anucleoside, a nucleotide, an oligonucleotide, a polymer, or, one or moreof two adjacent R¹-R⁴, R¹⁰, R^(10A), R^(10B), R^(10C) and R^(10D) are anindependently selected epoxide or cyclopropyl ring;

R⁵, R⁶ and R¹⁰ at the 5 (if present), 8, 9 and 14 positionsindependently are —H, —CH₃, —C₂H₅, —OH, —OR^(PR), —SR^(PR), —N(R^(PR))₂,—O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —N₃, —COOH, —OS(O)(O)OH, an ester,a thioester, a thionoester, a sulfite ester, a sulfate ester, asulfoxide, a sulfamate, a sulfonate, a sulfamide, a sulfinamide, asulfurous diamide, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate, a carbamate, ahalogen, an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety, an optionally substituted heteroarylmoiety, an optionally substituted heterocycle, an optionally substitutedmonosaccharide, an optionally substituted oligosaccharide, or, one, twoor more of R⁵, R⁶ and R¹⁰ at the 5, 8, 9 and 14 positions, together witha carbon atom that is adjacent to the carbon to which the R⁵, R⁶ or R¹⁰at the 5, 8, 9 or 14 position is bonded are an independently selectedepoxide or cyclopropyl ring;

R⁷ is —C(R¹⁰)₂—, —C(R¹⁰)₂—, —C(R¹⁰)₂—, —C(R¹⁰)₂—, —C(R¹⁰)₂—, —C(R¹⁰)₂—,—C(R¹⁰)₂—O—C(R¹⁰)₂—, —C(R¹⁰)₂—S—C(R¹⁰)₂—, —C(R¹⁰)₂—NR^(PR)—C(R¹⁰)₂—,—O—, —O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)—, —NH— or—NR^(PR)—C(R¹⁰)₂—;

R⁸ and R⁹ independently are —C(R¹⁰)₂—, —C(R¹⁰)₂—(R¹⁰)₂—, —O—,—O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—, or one orboth of R⁸ or R⁹ independently are absent, leaving a 5-membered ring;

R¹³ independently is C₁₋₆ alkyl; and

R^(PR) independently are —H, a protecting group or together are aprotecting group, wherein 0, 1, 2, 3 or 4 of R^(10A), R^(10B), R^(10C)and R^(10D) are —H, R⁵ and R⁶ respectively are in the β,β, α,β, β,α orα,α configurations, and wherein, R¹⁰ moieties at the 5 (if present), 8,9 and 14 positions respectively αre in the α,α,α,α, α,α,α,β, α,α,β,α,α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α,α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,α or β,β,β,β configurations. For any ofthe F1Cs of structure 5, 6, 7, 8, 9 or 10 where two variable groups arebonded to the same carbon, e.g., R¹, R², R³, R⁴ or R¹⁰ at the 11position, the each variable group at that position is independentlyselected.

In the F1Cs, each R¹, R², R³, R⁴, R¹⁰ at the 2, 11 and 15 positions, isindependently selected. In some embodiments one of the R¹, R², R³, R⁴,R¹⁰ at the 2, 11 and 15 positions is hydrogen and the other is —Hanother moiety, but usually 2, 3, 4, 5 or 6 of the remaining variablegroups are not —H, i.e., they are another moiety as defined for thosegroups. In other embodiments, both R¹, R², R³, R⁴, R¹⁰ at the 2, 11 and15 positions, are independently selected moieties other than hydrogen,i.e., they are another moiety as defined for those groups such as aC1-C20 organic moiety or C1-C20 optionally substituted alkyl group. Inmany embodiments R¹ at the 1-position in the β-configuration or R¹ atthe 1-position in the α-configuration is not —H and R⁴ at the 1-positionin the 6-configuration or R¹ at the 1-position in the α-configuration isnot —H.

Other embodiments of species and genera of F1Cs include compounds ofstructures B, C, D, E, F and G

where the dotted lines represent double or single bonds, each R^(10A),R^(10B), R^(10C), R^(10D), R^(10E) (when present), R^(10F), R^(10G) andR^(10H) is an independently selected single bonded R¹⁰ moiety in theα-configuration or the β-configuration, or each R^(10A), R^(10B),R^(10C) and R^(10D) is an independently selected double bonded R¹⁰moiety (e.g., ═O or ═CH₂), R^(1A) is a single bonded R¹ moiety in theα-configuration, or R^(1A) together with R¹ is a double bonded moiety(e.g., ═O, ═NOH, ═CH₂ or ═CH—CH₃), R^(2A) is a single bonded R² moietyin the α-configuration, or R^(2A) together with R² is a double bondedmoiety, R^(3B) is a single bonded R³ moiety in the β-configuration, orR^(3B) together with R³ is a double bonded moiety, or R^(3B) is absentif a double bond is present at the 16-17 position, R^(4A) is a singlebonded R⁴ moiety in the α-configuration, or R^(4A) together with R⁴ is adouble bonded moiety, or R^(4A) is absent if a double bond is present atthe 16-17 position, and R⁵, R⁶, R⁷, R⁸ and R⁹ are as previously defined.When a double bond is present at the 4-5 or the 5-6 positions, R^(10E)is absent. For these structures, R^(10A), R^(10B), R^(10C) and R^(10D)may be in the α,α, α,β, β,α, or β,β configurations respectively, whileR^(10E), R^(10F), R^(10G) and R^(10H) may be in the α,α,α,α, α,α,α,β,α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α,α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,α or β,β,β,βconfigurationsrespectively, typically the α,β,α,α or β,β,α,α configurations.

Thus, when R^(10E), R^(10F), R^(10G) and R^(10H) respecitively are inthe α,β,α,α configurations and R^(10A) and R^(10B) or R^(10A) andR^(10C) or R^(10A) and R^(10D) or R^(10B) and R^(10C) or R^(10B) andR^(10D) or R^(10C) and R^(10D) are both in α-configurations exemplary B,C, D, E, F and G structures include

Similarly, when R^(10E), R^(10F), R^(10G) and R^(10H) respectively arein the α,β,α,α configurations and R^(10A) and R^(10B) or R^(10A) andR^(10C) or R^(10A) and R^(10D) or R^(10B) and R^(10C) or R^(10B) andR^(10D) or R^(10C) and R^(10D) respectively are in the β,αconfigurations exemplary B, C, D, E, F and G structures include

When R^(10E), R^(10F), R^(10G) and R^(10H) respectively are in theα,β,α,α configurations and R^(10A) and R^(10B) or R^(10A) and R^(10C) orR^(10A) and R^(10D) or R^(10B) and R^(10C) or R^(10B) and R^(10D) orR^(10C) and R^(10D) respectively are in the α,β configurations exemplaryB, C, D, E, F and G structures include

When R^(10E), R^(10F), R^(10G) and R^(10H) respectively are in theα,β,α,α configurations and R^(10A) and R^(10B) or R^(10A) and R^(10C) orR^(10A) and R^(10D) or R^(10B) and R^(10C) or R^(10B) and R^(10D) orR^(10C) and R^(10D) respectively are in the β,β configurations exemplaryB, C, D, E, F and G structures include

When R^(10E), R^(10F), R^(10G) and R^(10H) respectively are in theβ,β,α,α configurations exemplary B, C, D, E, F and G structures include

When a double bond is present at the 5-6 position, and R^(10F), R^(10G)and R^(10H) respectively are in the β,α,α configurations exemplary B, C,D, E, F and G structures include

When a double bond is present at the 1-2 and 5-6 positions, and R^(10F),R^(10G) and R^(10H) respectively are in the β,α,α configurationsexemplary B, C, D, E, F and G structures include

When a double bond is present at the 5-6 and 16-17 positions, andR^(10F), R^(10G) and R^(10H) respectively are in the β,α,αconfigurations exemplary B, C, D, E, F and G structures include

Thus, exemplary F1C, e.g., 2, 5, 6, 7, 8, 9, 10, B, C, D, E, F and Gstructures are characterized as having the following:

(1) a double bond at the 5-6 position, no double bonds with R^(10E) atthe 5 position in the α-configuration, no double bonds with R^(10E) inthe β-configuration, a double bond at the 4-5 position, a double bond atthe 1-2 position with R^(10E) in the α-configuration, a double bond atthe 1-2 position with R^(10E) in the β-configuration, double bonds atthe 1-2 and 4-5 positions, double bonds at the 1-2 and 5-6 positions, adouble bond at the 16-17 position with R^(10E) in the α-configuration, adouble bond at the 16-17 position with R^(10E) in the β-configuration,double bonds at the 4-5 and 16-17 positions, double bonds at the 5-6 and16-17 positions, double bonds at the 1-2 and 16-17 positions withR^(10E) in the α-configuration, double bonds at the 1-2 and 16-17positions with R^(10E) in the β-configuration, double bonds at the 1-2,5-6 and 16-17 positions or double bonds at the 1-2, 4-5 and 16-17positions, and

(2) R^(10A), R^(10B), R^(10C) and R^(10D) are independently selected R¹⁰groups in the α,α, α,β, β,α, or β,β configurations respectively, and

(3) R^(10E), R^(10F), R^(10G) and R^(10H) are independently selected R¹⁰groups in the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β,α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β,β,β,β,α or β,β,β,βconfigurations respectively, and

(4) R^(1A), R^(2A), R^(3B) and R^(4A) are —H, R^(1A) is not —H andR^(2A), R^(3B) and R^(4A) are —H, R^(2A) is not —H and R^(1A), R^(3B)and R^(4A) are —H, R^(3B) is not —H and R^(1A), R^(2A) and R^(4A) are—H, R^(4A) is not —H and R^(1A), R^(2A) and R^(3B) are —H, R^(1A) andR^(2A) are not —H and R^(3B) and R^(4A) are —H, R^(1A) and R^(3B) arenot —H and R^(2A) and R^(4A) are —H, R^(1A) and R^(4A) are not —H andR^(2A) and R^(3B) are —H, R^(2A) and R^(3B) are not —H and R^(1A) andR^(4A) are —H, R^(2A) and R^(4A) are not —H and R^(1A) and R^(3B) are—H, R^(3B) and R^(4A) are not —H and R^(1A) and R^(2A) are —H, R^(1A),R^(2A) and R^(3B) are not —H and R^(4A) is —H, R^(1A), R^(2A) and R^(4A)are not —H and R^(3B) is —H, R^(1A), R^(3B) and R^(4A) are not —H andR^(2A) is —H, R^(2A), R^(3B) and R^(4A) are not —H and R^(1A) is —H,R^(1A), R^(2A), R^(3B) and R^(4A) are not —H, R^(1A) and R^(2A) are —Hand R^(3B) and R^(4A) are absent (i.e., a 16-17 double bond is present),R^(1A) is —H and R^(2A) is not —H and R^(3B) and R^(4A) are absent,R^(2A) is —H and R^(1A) is not —H and R^(3B) and R^(4A) are absent, or,R^(1A) and R^(2A) are not —H and R^(3B) and R^(4A) are absent, whereeach R^(1A), R^(2A), R^(3B) and R^(4A) are independently selected, and

(5) each R¹, R², R³ and R⁴ are independently selected.

For these exemplary formula B, C, D, E, F and G structures and any otherFiC structures disclosed herein, each R¹, R^(1A), R², R^(2A), R³,R^(3B), R⁴, R^(4A), R¹⁰, R^(10A), R^(10B), R^(10C), R^(10D), R^(10E),R^(10F) and R^(10G) are an independently selected atom or moiety asdescribed herein, e.g., —H, —OH, ═O, —SH, ═S, —F, —Cl, —Br, —I, —CN,—SCN, —N₃, —NH—C1-C8 optionally substituted alkyl, —N(C1-C8 optionallysubstituted alkyl)₂ where each optionally substituted alkyl moiety isthe same or different, protected ketone, e.g., ethylene ketal(—O—CH₂—CH₂—O—), —NO₂, —ONO₂, —(CH₂)_(n)—CH(O), —(CH₂)_(n)—COOH,—(CH₂)_(n)—COOR^(PR), —(CH₂)_(n)—NHCH₃, —(CH₂)_(n)—NHR^(PR), where n is1, 2, 3 or 4 and R^(PR) is —H or a protecting group, or a group such as:

optionally substituted alkyl, e.g., —CH₃, —C₂H₅, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃,—CH₂CH₂OCH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CHOHCH₃,—CH(OC(O)CH₃)—CH₃, —CH(OR^(PR))—CH₃, —CF₃, —(CH₂)_(t)—NH₂, —(CH₂)₂—NH₂,—(CH₂)₃—NH₂, —CH₂—NHCH₃, —(CH₂)₂—NHCH₃, —(CH₂)₃—NHCH₃,—(CH₂)_(t)—N(CH₃)₂, —(CH₂)_(n)—CH₂OH, where n is 1, 2, 3 or 4 and R^(PR)is —H or a protecting group, or

optionally substituted alkenyl, e.g., —CH═CH₂, —CH═CHF, —CH═CHCl,—CH═CHBr, —CH═CHI, —CH═CH—(CH₂)_(n)—OH, —CH═NCH₃, —CH═NR^(PR),—CH═N—CH₃, —CH═CH—CH₃, —CH═CH—(CH₂)_(n)—COOR^(PR),—CH═CH—(CH₂)_(n)—NHR^(PR), —CH═CH—CH₂—OR^(PR), where R^(PR) is —H or aprotecting group, or

optionally substituted alkynyl, e.g., —C≡CH, —C≡C—(CH₂)_(m)—OH,—C≡C-halogen, —C≡C—CH₃, —C≡CCF₃, —C≡CCH₂F, —C≡CCH₂Cl, —C≡CCH₂Br,—C≡CCH₂I, —C≡C—CH₂OH, —C≡C—CH₂-halogen, —C≡C—CH₂—C(O)OR^(PR),—C≡C—CH₂—CH₃, —C≡C—CH₂—CH₂OH, —C≡C—(CH₂)_(n)—C₆H₅,—C≡C—(CH₂)_(n)—C₆H₄COOR^(PR), —C≡C—(CH₂)_(n)—C₆H₄COOR^(PR),—C≡C—(CH₂)_(n)—C₆H₃(OH)₂, —C≡C—(CH₂)_(n)—C₆H₄F, —C≡C—(CH₂)_(n)—C₆H₄Br,—C≡C—CH₂—CH₂—C(O)OR^(PR), —C≡C—(CH₂)_(n)—CH₃,—C≡C—CH(CH₃)—(CH₂)_(n)—CH₃, —C≡C—(CH₂)_(n)—CHOR^(PR),—C≡C—CH(CH₃)—(CH₂)_(n)—CHOR^(PR), —C≡C—(CH₂)_(n)—CHCOOR^(PR),—C≡C—CH(CH₃)—(CH₂)_(n)—NHR^(PR), —C≡C—(CH₂)_(n)—NHR^(PR),—C≡C—(CH₂)_(n)—C(O)NHR^(PR), where n is 0, 1, 2, 3, 4, 5 or 6, n is 1,2, 3 or 4 and R^(PR) is —H or a protecting group, or

optionally substituted aryl, optionally substituted alkylaryl,optionally substituted alkenylaryl or optionally substitutedalkynylaryl, e.g., optionally substituted phenyl, optionally substitutedbenzyl, —(CH₂)_(n)—C₆H₄OH, —(CH₂)_(n)—C₆H₄OR^(PR), —(CH₂)_(n)—C₆H₃(OH)₂,—(CH₂)_(n)—C₆H₄F, —(CH₂)_(n)—C₆H₄Br, —(CH₂)_(n)—C₆H₄C(O)OR^(PR),—(CH₂)_(n)—C₆H₄C(O)SR^(PR), or analogs where the aromatic ring contains1, 2, 3 or 4 independently chosen substituents such as independentlychosen halogen, —OH, —SH, —NO₂, —CN, —SCN, —N₃, C1-C6 ester, C1-C6alkyl, C1-C6 ether, C1-C6 thioether, —OR^(PR), —(CH₂)_(n)—C(O)OR^(PR),—(CH₂)_(n)—NHR^(PR), —(CH₂)_(n)—OR^(PR) or—(CH₂)_(m)—O—(CH₂)_(m)—OR^(PR) where n is 0, 1, 2, 3, 4, 5 or 6, mindependently are 1, 2 or 3 and R^(PR) independently are —H or aprotecting group, or

ether, e.g., optionally substituted alkoxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedaryloxy, —OCH₃, —OC₂H₅, —OC₃H₇, —OC₄H₉, —OC₂H₃, —OC₃H₅, —OC₄H₇,—O—C(CH₃)₃, —OCH₂CH₂OH, —O(CH₂)₂—O—CH₃, —O(CH₂)₃—O—CH₃, —O—CH(CH₃)CH₃,—O—CH₂CH₂CH₃, —O—C1-C20 organic moiety where the organic moiety is,e.g., —CH₃, —C₂H₅, i-propyl, n-propyl, t-butyl, n-butyl, l-butyl,n-hexyl, n-octyl, n-decyl, —(CH₂)₁₋₈—OH, —CHO, —(CH₂)₁₋₈—NH₂,—(CH₂)₁₋₈—C(O)—OH, or

ester, e.g., —OC(O)CH₃, —OC(O)C₂H₅, —OC(O)C₂H₃, —OC(O)CH₂CH₂CH₃,—OC(O)CH(CH₃)₂, —O—C(O)—(CH₂)₂—C(O)OH, —O—C(O)—(CH₂)₂—C(O)OR^(PR),—OC(O)—(CH₂)_(m)—CH₃, —OC(O)C₆H₅, —OC(O)CH₂C₆H₅, a C2-C20 ester such as—O—C(O)—CH₃, —O—C(O)—CF₃, —O—C(O)—CCl₃, —O—C(O)—C₂H₅, —O—C(O)—C₄H₇,—O—C(O)—C₆H₅, —O—C(O)—(CH₂)₂—CH₃, —O—C(O)—(CH₂)₃—CH₃,—O—C(O)—(CH₂)₄—CH₃, —O—C(O)—(CH₂)₅—CH₃, —O—C(O)—(CH₂)₆—CH₃, —O—C(O)-2furanyl, —O—C(O)-2 thiophenyl, —O—C(O)-2 pyrrolyl, —O—C(O)-2pyrimidinyl, —O—C(O)-3 pyrimidinyl, —O—C(O)-2 pyridyl, —O—C(O)-3pyridyl, —O—C(O)-heterocycle, —O—C(O)—(CH₂)_(m)—C(O)O—C1-C10 optionallysubstituted alkyl, —O—C(O)—C₁₋₁₂ optionally substituted alkyl,—OC(O)—(CH₂)_(q)—C(O)OH, —OC(O)—(CH₂)_(q)—C(O)O—C₁₋₈ optionallysubstituted alkyl, where the optionally substituted alkyl optionally ismethyl, ethyl, i-propyl, n-propyl, t-butyl, n-butyl, n-hexyl, n-octyl,n-decyl, —CH₂OH, —CH₂OR^(PR), —(CH₂)_(n)—CH₃, —(CH₂)_(n)—OH,—(CH₂)_(n)—Br, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—O—CH₃, —CF₃, wherein R^(PR) independently are —H, aprotecting group such as C1-C10 optionally substituted alkyl (e.g.,—CH₃, —C₂H₅, —C₃H₆OH) or together are a protecting group, m is 0, 1, 2,3, 4, 5 or 6 and q is 0, 1, 2, 3, 4, 5 or 6, or

optionally substituted amine, e.g., —NH₂, —NH₃ ⁺Cl⁻, —NH₃ ⁺Br⁻, —NH₃⁺I⁻, alkylamine, dialkylamine, —NH—CH₃, —N(CH₃)₂, —N⁺(CH₃)₃, —N⁺(C₂H₅)₃,—NHOH, —NHR^(PR), —N(R^(PR))₂, —NH—C(O)CH₃, —NH—C(O)CF₃, —N(C(O)CF₃)₂,—NH—C(O)CCl₃, —N(C(O)CCl₃)₂, —NH—C(O)C₆H₅, —N(C(O)C₆H₅)₂, —NH—C₂H₅,—N(C₂H₅)₂, —NH—CH₂OH, —NH—CH₂—CH₂OH, —NH—C₃H₇,—NH—C(═NH)—N(CH₃)—CH₂—C(O)OR^(PR), —N(CH₃)₂, —N(C₂H₅)₂,—N(CH₃)(C₂H₅)—N(CH₂OH)(CH₃), —N═C[(CH₂)_(n)—H]—OH,—NH—NH—C(O)-optionally substituted alkyl, —NH—C(NH-optionallysubstituted alkyl)=N-optionally substituted alkyl,—N═C[(CH₂)_(n)—H]-O-optionally substituted alkyl, —NH-organic moiety,—NH—C(O)-organic moiety, e.g., —NH—C(O)—CH₃, —NH—(CH₂)_(n)-optionallysubstituted phenyl, —NH-optionally substituted alkyl, —N(optionallysubstituted alkyl)₂, —N(C(O)-optionally substituted alkyl)₂,—NH—C(O)-optionally substituted alkyl or —NH—(CH₂)_(n)-optionallysubstituted alkyl, or

optionally substituted amide, e.g., —C(O)—NH₂, —C(O)—NH—C(CH₃)₃,—C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—NH—(CH₂)_(m)—CH₃, —C(O)—NH—(CH₂)_(m)—NH₂,—C(O)—NH—(CH₂)_(m)—NHR^(PR), —NH—C(O)H, —NH—C(O)—CH₂—CH₂—C(O)OH,—NH—C(O)—CH₂—CH₂—C(O)OR^(PR), —NH—C(O)—(CH₂)_(m)—C(O)OH,—NH—C(O)—(CH₂)_(m)—C(O)OR^(PR), —NH—C(O)—CH₃, —NH—C(O)—(CH₂)_(m)—NH₂,—NH—C(O)—(CH₂)_(m)—NHR^(PR), —NH—C(O)—O—C(CH₃)₃, —NH—C(O)—O—CH₃,—C(O)—NH-organic moiety, —C(O)—NH-optionally substituted alkyl,—C(O)—NR⁴⁹—(O)_(p)-organic moiety, —C(O)—NH—(O)_(p)(CH₂)_(n)-optionallysubstituted phenyl, —C(O)—NH—(CH₂)_(n)—(O)_(p)-optionally substitutedalkyl, —NH—C(O)—(O)_(p)-optionally substituted alkyl,—NH—C(S)—(O)_(p)-optionally substituted alkyl, wherein m independentlyare 1, 2, 3, 4, 5 or 6, n independently are 0, 1, 2, 3 or 4 and p is 0or 1, or

—O—Si(C1-C6 alkyl)₃ where each alkyl is independently chosen, e.g.,—O—Si(CH₃)₃, —O—Si[C(CH₃)₃](CH₃)₂, —O—Si[C(CH₃)₃](C₂H₅)₂, or

optionally substituted heterocycle or —O—[C(O)]_(m)—(CH₂)_(n)-optionallysubstituted heterocycle, —(CH₂)_(n)-optionally substituted heterocycle,e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl,3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl,3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl or 1-piperidinyl, wherein m is 0 or 1 and n is 0, 1, 2 or 3,e.g., m and n are both 0, m is 1 and n is 0, m is 0 and n is 1, m and nare both 1, or

carboxyl which is optionally substituted, e.g., —C(O)OH, —C(O)OR^(PR),—C(O)OM, —C(O)O—CH₃, —C(O)—O—(CH₂)_(n)—CH₃, —C(O)O-organic moiety,—C(O)O—(CH₂)_(n)-optionally substituted phenyl or—C(O)O—(CH₂)_(n)-optionally substituted alkyl, wherein the phenyl oralkyl moieties are optionally substituted with 1, 2 or 3 independentlyselected with substituents described herein, e.g., —F, —Cl, —Br, —I,—OH, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —NO₂, —CN, —SCN, —NH₂, —C(O)OR^(PR)or —(CH₂)₁₋₄—C(O)—OR^(PR), where n is 0, 1, 2, 3, 4, 5 or 6, R^(PR) is—H or a protecting group such as methyl, ethyl, propyl or butyl, and Mis a metal such as an alkali metal, e.g., Li⁺, Na⁺ or K⁺ or M is anothercounter ion such as an ammonium ion, or

carbonate, e.g., —O—C(O)—O—CH₃, —O—C(O)—O—(CH₂)_(n)—CH₃,—O—C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₃, —O—C(O)—O-organic moiety,—O—C(O)—C(CH₂)_(n)-optionally substituted phenyl or—C(O)—O—(CH₂)_(n)-optionally substituted alkyl, or

carbamate, e.g., —O—C(O)—NH₂, —O—C(O)—NH—CH₃, —O—C(O)—NH—C₂H₅,—O—C(O)—NH—C₃H₇, —O—C(O)—NH—C₄H₉, —O—C(O)—NH—C₂H₃, —O—C(O)—NH—C₃H₅,—O—C(O)—NH—C₄H₇, —O—C(O)—NHR^(PR), —O—C(O)—NH-organic moiety,—O—C(O)—NR⁴⁸-organic moiety, —NH—C(O)—O-organic moiety,—NR⁴⁸—C(O)—O-organic moiety, wherein the organic moiety is as describedherein, or

optionally substituted oxime, e.g., ═NOH, ═NOCH₃, ═NOC₂H₅, ═NOC₃H₇,═N—(CH₂)_(n)—(X)_(q)—(CH₂)_(n)-optionally substituted alkyl, where X is—O—, —C(O)—, —S— or —NH— and the optionally substituted alkyl moiety isas described herein,

an acetal or spiro ring, e.g., —O—CH₂—O—, —O—(CH₂)₂—O—, —O—(CH₂)₃—O— or—[C(R³⁶)₂]₁₋₄—O—, —O—C(O)—CH₂—, —O—C(O)—CH₂—CH₂—, —O—C(O)—CH₂—CH₂—CH₂—,—O—C(O)—CHR¹⁰—, —O—C(O)—CHR¹⁰—CHR¹⁰—, —O—C(O)—(CHR¹⁰)₃—, —NH—(CH₂)₂—O—,—NH—(CH₂)₂—NH—, —NH—(CH₂)₂—S—, —CH₂—N═CH—NH—, —NH—(CH₂)₃—O—,—NH—(CH₂)₃—S—, —NH—(CH₂)₃—O—, where R¹⁰ are independently selected andoptionally independently are —H, —F, —Cl, —Br, —I, —CH₃, —C₂H₅, —CF₃,—C₂F₅, —CH₂CF₃, —OH, —CN, —SCN, —OCH₃ or —OC₂H₅, and where each R³⁶independently is —H, —F, —Cl, —Br, —I or an organic moiety such asC1-C10 optionally substituted alkyl (e.g., methyl or ethyl), C2-10alkenyl, aryl or a heterocycle, any of which are optionally substitutedas described herein, e.g., —CF₃ or —CH₂OH, or

thioacetal, e.g., —S—CH₂—O—, —S—(CH₂)₂—O—, —S—(CH₂)₃—O—, —S—CH₂—S—,—S—(CH₂)₂—S—, —S—(CH₂)₃—S— or —S—[C(R³⁶)₂]₁₋₄—S— where each R³⁶independently is —H, —F, —Cl, —Br, —I or an organic moiety such asC1-C10 optionally substituted alkyl (e.g., methyl or ethyl), C2-10alkenyl, aryl or a heterocycle, any of which are optionally substitutedas described herein, e.g., —CF₃ or —CH₂OH.

For any of these exemplary F1C, e.g., the B, C, D, E, F and Gstructures, some embodiments are characterized by the presence of one ortwo independently selected substitutions at R^(10A), R^(10B), R^(10C)and R^(10D) and optionally:

(a) R^(10E) (when present at the 5-position), R^(10F), R^(10G) andR^(10H) are independently selected R¹⁰ groups in the α,β,α,α or β,β,α,αconfigurations respectively, R¹ is an oxygen-bonded, nitrogen-bonded ora sulfur-bonded moiety such as —OH, ═O, —SH, ═NOH, —NH(C1-C8 optionallysubstituted alkyl), an ester, an ether, a thioester, or a thioether,R^(1A) is —H, absent, a carbon-bonded moiety such as an acyl moiety,optionally substituted alkyl or optionally substituted alkylaryl, R² isa halogen or an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H,absent, a carbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent, a carbon-bonded moiety, R⁴is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R^(4A) is —H,absent, a carbon-bonded moiety such as an acyl moiety, optionallysubstituted alkyl or optionally substituted alkylaryl,

(b) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R^(1A) is —H, an oxygen-bonded, nitrogen-bonded or asulfur-bonded moiety, R¹ is —H, a carbon-bonded moiety, R² is a halogenor an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent, acarbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent, a carbon-bonded moiety, R⁴is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R^(4A) is —H,absent or a carbon-bonded moiety,

(c) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R¹ is an oxygen-bonded, nitrogen-bonded or a sulfur-bondedmoiety, R^(1A) is —H, absent or a carbon-bonded moiety, R² is a halogenor an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent or acarbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent or a carbon-bonded moiety,R^(4A) is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R⁴ is—H, a halogen or a carbon-bonded moiety,

(d) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R¹ is an oxygen-bonded, nitrogen-bonded or a sulfur-bondedmoiety, R^(1A) is —H, absent, a carbon-bonded moiety, R² is a halogen oran oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent or acarbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent or a carbon-bonded moiety, R⁴is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R^(4A) is —H,absent or a carbon-bonded moiety,

(e) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R¹ is an oxygen-bonded, nitrogen-bonded or a sulfur-bondedmoiety, R^(1A) is —H, absent or a carbon-bonded moiety, R² is a halogenor an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent or acarbon-bonded moiety, R^(3B) is a halogen or an oxygen-bonded or asulfur-bonded moiety, R³ is —H, a carbon-bonded moiety, R⁴ is a halogen,an oxygen-bonded or a sulfur-bonded moiety, R^(4A) is —H, absent or acarbon-bonded moiety,

(f) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R^(1A) is —H, an oxygen-bonded, nitrogen-bonded or asulfur-bonded moiety, R¹ is —H, a carbon-bonded moiety, R² is a halogenor an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent or acarbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent or a carbon-bonded moiety,R^(4A) is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R⁴ is—H, a carbon-bonded moiety, or

(g) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R¹ is a halogen or an oxygen-bonded, nitrogen-bonded,carbon bonded or a sulfur-bonded moiety, R^(1A) is —H, a carbon-bondedor nitrogen-bonded moiety and R², R^(2A), R³R^(3B), R⁴ and R^(4A) are asdescribed any of in the foregoing embodiments or elsewhere herein. Inany of these embodiments, R⁵-R⁹ are independently selected moieties asdescribed herein and the oxygen-bonded, nitrogen-bonded, carbon bondedor sulfur-bonded moieties at R¹, R^(1A), R², R^(2A), R³, R^(3B), R⁴, andR^(4A) include atoms or groups described herein. These embodimentscontain formula B, C, D, E, F and G compounds wherein one or two of R¹,R^(1A), R², R^(2A), R³, R^(3B), R⁴, and R^(4A) are independentlyselected nitrogen-bonded moieties, one, two or three of R¹, R^(1A), R²,R^(2A), R³, R^(3B), R⁴, and R^(4A) are independently selectedcarbon-bonded moieties and one, two, three, four or five of R², R^(2A),R³, R^(3B), R⁴, and R^(4A) are independently selected or halogen atomsor oxygen-bonded or sulfur-bonded moieties.

These embodiments contain F1C, such as the B, C, D, E, F and Gstructures wherein R⁴ and R^(4A) are present, i.e., no 16-17 double bondis present, and both are the same, such as optionally substituted alkyl,halogen, ether, ester, thioether, thioester, e.g., —OR^(PR), —SR^(PR),—F, —Cl, —Br, —I, methyl, ethyl, methoxy, ethoxy acetate or propionate.However, in many embodiments, when they are both present, R⁴ and R^(4A)are two independently selected dissimilar moieties defined herein, e.g.,independently selected —H, —OH, —OR^(PR), an ester (e.g., —OC(O)—CH₃,—OC(O)—C₂H₅, —OC(O)—C3 alkyl, —OC(O)—C4 alkyl,), ether (e.g., —OCH₃,—OC₂H₅, —OCH₂CH₂CH₃, or —OCH(CH₃)CH₃, —O—C4 alkyl, —O—C5 alkyl or —O—C6alkyl), a thioester, a thioether, an acyl moiety, a carbonate, acarbamate an amide, a monosaccharide, a disaccharide, or an amino acid,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl or another moiety described herein.

For any F1C, examples of dissimilar R⁴ and R^(4A) moieties at the17-position include (α-ester, β-optionally substituted alkynyl),(β-ester, α-optionally substituted alkynyl), α-thioester, β-optionallysubstituted alkynyl), (β-thioester, α-optionally substituted alkynyl),(α-ester, β-optionally substituted alkenyl), (β-ester, α-optionallysubstituted alkenyl), α-thioester, β-optionally substituted alkenyl),(β-thioester, α-optionally substituted alkenyl), (α-optionallysubstituted alkyl, β-ester), (β-optionally substituted alkyl, α-ester),α-optionally substituted alkyl, β-optionally substituted amine),(β-optionally substituted alkyl, α-optionally substituted amine),(α-optionally substituted alkyl, β-halogen)-, (β-optionally substitutedalkyl, α-halogen), (α-halogen, β-optionally substituted alkyl),(β-halogen, α-optionally substituted alkyl), (β-ester, α-acyl),(α-ester, β-acyl), (β-ester, α-C(O)—C1-C10 optionally substitutedalkyl), (α-ester, β-C(O)—C1-C10 optionally substituted alkyl),(β-thioester, α-C(O)—C1-C10 optionally substituted alkyl), (βOH,α-ester), (α-OH, β-ester), (β-OH, α-ether), (α-OH, β-ether), (β-OH,α-acyl), (α-OH, β-acyl), (α-F, β-optionally substituted alkyl), (β-F,α-optionally substituted alkyl), (α-OH, β-optionally substitutedalkynyl), (β-OH, α-optionally substituted alkynyl), (α-OH,β-C≡CCH₂-halogen), (β-OH, α-C≡CCH₂-halogen), (α-OH, β-C≡C-halogen),(β-OH, α-C≡C-halogen), (α-cyclopropyl, β-optionally substituted alkylwhere the epoxy is formed with an adjacent steroid nucleus atom),(β-cyclopropyl, α-optionally substituted alkyl), (α-optionallysubstituted alkyl, β-NH—C1-C8 optionally substituted alkyl),(β-optionally substituted alkyl, α-NH—C1-C8 optionally substitutedalkyl), (α-ether, β-NH—C1-C8 optionally substituted alkyl), (α-C(O)CH₃,β-NH—C1-C8 optionally substituted alkyl), (β-C(O)CH₃, α-NH—C1-C8optionally substituted alkyl), and other combinations of groups that arewithin the scope of R⁴ and R^(4A). Such moieties, which are the same ordifferent can also be at 1, 2, 3 or more R¹ and R^(1A), R² and R^(2A),R³ and R^(3B) variable groups, and/or the R¹⁰ variable groups at R⁷, R⁸and R⁹.

Specific dissimilar R⁴ and R^(4A) moieties include, e.g., (α-F, β-CH₃),(β-F, α-CH₃), (α-F, β-C₂H₅), (β-F, α-C₂H₅), (α-F, β-CH₃), (β-F, α-CH₃),(α-Br, β-CH₃), (β-Br, α-CH₃), (α-OH, β-CCCH₃), (β-OH, α-CCCH₃), (α-OH,β-CCCH₂OH), (β-OH, α-CCCH₂OH), (α-OH, β-CCH), (β-OH, α-CCH), (α-CH₃,β-OC(O)CH₃), (β-CH₃, α-OC(O)CH₃), (α-C₂H₅, β-OC(O)CH₃), (β-C₂H₅,α-OC(O)CH₃), (α-C₃H₇, β-OC(O)CH₃), (β-C₃H₇, α-OC(O)CH₃), (α-C₄H₉,β-OC(O)CH₃), (β-C₄H₉, α-OC(O)CH₃), (α-C₂H₃, β-OC(O)CH₃), (β-C₂H₃,α-OC(O)CH₃), (α-C₂H₄OH, β-OC(O)CH₃), (β-C₂H₄OH, α-OC(O)CH₃), (α-C₃H₅,(β-OC(O)CH₃), (β-C₃H₅, α-OC(O)CH₃), (α-C₄H₇, β-OC(O)CH₃), (β-C₄H₇,α-OC(O)CH₃), (α-C₃H₃, β-OC(O)CH₃), (β-C₃H₃, α-OC(O)CH₃), (α-C₄H₅,β-OC(O)CH₃), (β-C₄H₅, α-OC(O)CH₃), (α-CH₃, β-OC(O)C₂H₅), (β-CH₃,α-OC(O)C₂H₅), (α-C₂H₅, β-OC(O)C₂H₅), (β-C₂H₅, α-OC(O)C₂H₅), (α-C₃H₇,(β-OC(O)C₂H₅), (β-C₃H₇, α-OC(O)C₂H₅), (α-C₄H₉, (β-OC(O)C₂H₅), (βC₄H₉,α-OC(O)C₂H₅), (α-C₂H₃, β-OC(O)C₂H₅), (β-C₂H₃, α-OC(O)C₂H₅), (α-C₂H₄OH,β-OC(O)C₂H₅), (β-C₂H₄OH, α-OC(O)C₂H₅), (α-C₃H₅, β-OC(O)C₂H₅), (β-C₃H₅,α-OC(O)C₂H₅), (α-C₄H₇, β-OC(O)C₂H₅), (β-C₄H₇, α-OC(O)C₂H₅), (α-C₃H₃,β-OC(O)C₂H₅), (β-C₃H₃, α-OC(O)C₂H₅), (α-C₄H₅, β-OC(O)C₂H₅), (β-C₄H₅,α-OC(O)C₂H₅), (α-C(O)CH₃, β-OC(O)CH₃), (β-C(O)CH₃, α-OC(O)CH₃),(α-C(O)C₂H₅, β-OC(O)CH₃), (β-C(O)C₂H₅, α-OC(O)CH₃), (α-C(O)CH₃,β-NH—CH₃) and (β-C(O)CH₃, α-NH—CH₃)

Additional embodiments of the F1Cs include any F1Cs or any 2, 5, 6, 7,8, 9, 10, B, C, D, E, F or G structures, e.g., any of the F1Cs or F1Cgenera disclosed herein, wherein one or both of R⁵ or R⁶ independentlyare —H, —CH₂SH, —CHO, —CH₂NR^(PR), —CH₂NH₂, —C₄H₉, —C₃H₇, —C₂H₅, —CH₃,—C₂H₄OH, —C₂H₄SH, —C₂H₄NH₂, —CH₂CHO, —CH₂CH₂NR^(PR), —CH₂CH₂OH,—CH₂CH₂SH, —CH₂CH₂C₆H₅, —CH₂C₆H₅, —C₆H₅ or optionally substituted alkylwherein any phenyl (C₆H₅) moiety in the foregoing groups is optionallysubstituted at the phenyl ring with 1, 2, 3, 4 or 5 moietiesindependently selected from those described for esters herein andincluding C1-C6 alkyl (optionally substituted with 1 or 2 independentlyselected —OH, —SH, —O—, —S— or —NH—) C1-C6 alkoxy, —F, —Cl, —Br, —I,—CN, —NO₂, —OH, —SH, —COOR^(PR), —NHR^(PR) and —C(O)—C1-C6 alkyl.Typically R⁵ or R⁶ are both in the β-configuration, but they may be in,e.g., the α,β or β,α configurations respectively.

Specific F1Cs that can be used in the clinical treatments and othermethods described herein include the following groups of compounds.

Group 1. Exemplary embodiments include the formula 1 compounds namedaccording to the compound structure designations given in Tables A and Bbelow. Each compound named in Table B is depicted as a compound havingformula B

where R⁵ and R⁶ are both —CH₃, there is no double bond at the 1-2-,4-5-, 5-6 or 16-17 positions, R⁷, R⁸ and R⁹ are all —CH₂—, R^(10A),R^(10B), R^(10C), R^(10D), R^(10E), R^(10F), R^(10G) and R^(10H) are all—H and R¹, R², R³ and R⁴ are the substituents designated in Table A. Thecompounds named according to Tables A and B are referred to as “group 1”compounds.

Compounds named in Table B are named by numbers assigned to R¹, R², R³and R⁴ according to the following compound naming convention, R¹, R²,R³, R⁴, using the numbered chemical substituents in Table A. Each TableA number specifies a different structure for each of R¹, R², R³ and R⁴.When R¹, R², R³ or R⁴ is a divalent moiety, e.g., ═O, the hydrogen atthe corresponding position is absent. Thus, the group 1 compound named1.2.1.1 is a formula B structure with a β-hydroxyl bonded to carbons atthe 3- and 7-positions (the variable groups R¹ and R² respectively), anα-bromine bonded to carbon 16 (the variable group R³) and double bondedoxygen (═O) at carbon 17 (the variable group R⁴), i.e., 1.2.4.1 is3β,7β-dihydroxy-16α-fluoro-17β-aminoandrostane and has the structure

Similarly, group 1 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-aminoandrostane and compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17β-aminoandrostane.

TABLE A R¹ R² 1 —OH 1 —H 2 ═O 2 —OH 3 —SH 3 ═O 4 ═S 4 —CH₃ 5 —NH₂ 5—OCH₃ 6 —NH—C(O)CH₃ 6 —F 7 —H 7 —Cl 8 —CH₃ 8 —Br 9 —O—S(O)(O)—OC₂H₅ 9 —I10 —O—S(O)(O)—O⁻Na⁺ 10 ═CH₂ R³ R⁴ 1 —Br 1 —NH₂ 2 —Cl 2 —NH—C(O)CH₃ 3 —I3 ═NOH 4 —F 4 —NH—CH₃ 5 —H 5 —N(CH₃)₂ 6 —OH 6 —N⁺(CH₃)₃ 7 ═O 7 —NH—C₂H₅8 —O—C(O)—CH₃ 8 —NHOH 9 —O—C(O)—CH₂CH₃ 9 —OH 10 ═CH₂ 10 ═O

TABLE B 1.1.1.1, 1.1.1.2, 1.1.1.3, 1.1.1.4, 1.1.1.5, 1.1.1.6, 1.1.1.7,1.1.1.8, 1.1.1.9, 1.1.1.10, 1.1.2.1, 1.1.2.2, 1.1.2.3, 1.1.2.4, 1.1.2.5,1.1.2.6, 1.1.2.7, 1.1.2.8, 1.1.2.9, 1.1.2.10, 1.1.3.1, 1.1.3.2, 1.1.3.3,1.1.3.4, 1.1.3.5, 1.1.3.6, 1.1.3.7, 1.1.3.8, 1.1.3.9, 1.1.3.10, 1.1.4.1,1.1.4.2, 1.1.4.3, 1.1.4.4, 1.1.4.5, 1.1.4.6, 1.1.4.7, 1.1.4.8, 1.1.4.9,1.1.4.10, 1.1.5.1, 1.1.5.2, 1.1.5.3, 1.1.5.4, 1.1.5.5, 1.1.5.6, 1.1.5.7,1.1.5.8, 1.1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5,1.1.6.6, 1.1.6.7, 1.1.6.8, 1.1.6.9, 1.1.6.10, 1.1.7.1, 1.1.7.2, 1.1.7.3,1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.7.8, 1.1.7.9, 1.1.7.10, 1.1.8.1,1.1.8.2, 1.1.8.3, 1.1.8.4, 1.1.8.5, 1.1.8.6, 1.1.8.7, 1.1.8.8, 1.1.8.9,1.1.8.10, 1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4, 1.1.9.5, 1.1.9.6, 1.1.9.7,1.1.9.8, 1.1.9.9, 1.1.9.10, 1.1.10.1, 1.1.10.2, 1.1.10.3, 1.1.10.4,1.1.10.5, 1.1.10.6, 1.1.10.7, 1.1.10.8, 1.1.10.9, 1.1.10.10, 1.2.1.1,1.2.1.2, 1.2.1.3, 1.2.1.4, 1.2.1.5, 1.2.1.6, 1.2.1.7, 1.2.1.8, 1.2.1.9,1.2.1.10, 1.2.2.1, 1.2.2.2, 1.2.2.3, 1.2.2.4, 1.2.2.5, 1.2.2.6, 1.2.2.7,1.2.2.8, 1.2.2.9, 1.2.2.10, 1.2.3.1, 1.2.3.2, 1.2.3.3, 1.2.3.4, 1.2.3.5,1.2.3.6, 1.2.3.7, 1.2.3.8, 1.2.3.9, 1.2.3.10, 1.2.4.1, 1.2.4.2, 1.2.4.3,1.2.4.4, 1.2.4.5, 1.2.4.6, 1.2.4.7, 1.2.4.8, 1.2.4.9, 1.2.4.10, 1.2.5.1,1.2.5.2, 1.2.5.3, 1.2.5.4, 1.2.5.5, 1.2.5.6, 1.2.5.7, 1.2.5.8, 1.2.5.9,1.2.5.10, 1.2.6.1, 1.2.6.2, 1.2.6.3, 1.2.6.4, 1.2.6.5, 1.2.6.6, 1.2.6.7,1.2.6.8, 1.2.6.9, 1.2.6.10, 1.2.7.1, 1.2.7.2, 1.2.7.3, 1.2.7.4, 1.2.7.5,1.2.7.6, 1.2.7.7, 1.2.7.8, 1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2, 1.2.8.3,1.2.8.4, 1.2.8.5, 1.2.8.6, 1.2.8.7, 1.2.8.8, 1.2.8.9, 1.2.8.10, 1.2.9.1,1.2.9.2, 1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6, 1.2.9.7, 1.2.9.8, 1.2.9.9,1.2.9.10, 1.2.10.1, 1.2.10.2, 1.2.10.3, 1.2.10.4, 1.2.10.5, 1.2.10.6,1.2.10.7, 1.2.10.8, 1.2.10.9, 1.2.10.10, 1.3.1.1, 1.3.1.2, 1.3.1.3,1.3.1.4, 1.3.1.5, 1.3.1.6, 1.3.1.7, 1.3.1.8, 1.3.1.9, 1.3.1.10, 1.3.2.1,1.3.2.2, 1.3.2.3, 1.3.2.4, 1.3.2.5, 1.3.2.6, 1.3.2.7, 1.3.2.8, 1.3.2.9,1.3.2.10, 1.3.3.1, 1.3.3.2, 1.3.3.3, 1.3.3.4, 1.3.3.5, 1.3.3.6, 1.3.3.7,1.3.3.8, 1.3.3.9, 1.3.3.10, 1.3.4.1, 1.3.4.2, 1.3.4.3, 1.3.4.4, 1.3.4.5,1.3.4.6, 1.3.4.7, 1.3.4.8, 1.3.4.9, 1.3.4.10, 1.3.5.1, 1.3.5.2, 1.3.5.3,1.3.5.4, 1.3.5.5, 1.3.5.6, 1.3.5.7, 1.3.5.8, 1.3.5.9, 1.3.5.10, 1.3.6.1,1.3.6.2, 1.3.6.3, 1.3.6.4, 1.3.6.5, 1.3.6.6, 1.3.6.7, 1.3.6.8, 1.3.6.9,1.3.6.10, 1.3.7.1, 1.3.7.2, 1.3.7.3, 1.3.7.4, 1.3.7.5, 1.3.7.6, 1.3.7.7,1.3.7.8, 1.3.7.9, 1.3.7.10, 1.3.8.1, 1.3.8.2, 1.3.8.3, 1.3.8.4, 1.3.8.5,1.3.8.6, 1.3.8.7, 1.3.8.8, 1.3.8.9, 1.3.8.10, 1.3.9.1, 1.3.9.2, 1.3.9.3,1.3.9.4, 1.3.9.5, 1.3.9.6, 1.3.9.7, 1.3.9.8, 1.3.9.9, 1.3.9.10,1.3.10.1, 1.3.10.2, 1.3.10.3, 1.3.10.4, 1.3.10.5, 1.3.10.6, 1.3.10.7,1.3.10.8, 1.3.10.9, 1.3.10.10, 1.4.1.1, 1.4.1.2, 1.4.1.3, 1.4.1.4,1.4.1.5, 1.4.1.6, 1.4.1.7, 1.4.1.8, 1.4.1.9, 1.4.1.10, 1.4.2.1, 1.4.2.2,1.4.2.3, 1.4.2.4, 1.4.2.5, 1.4.2.6, 1.4.2.7, 1.4.2.8, 1.4.2.9, 1.4.2.10,1.4.3.1, 1.4.3.2, 1.4.3.3, 1.4.3.4, 1.4.3.5, 1.4.3.6, 1.4.3.7, 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10.3.1.6,10.3.1.7, 10.3.1.8, 10.3.1.9, 10.3.1.10, 10.3.2.1, 10.3.2.2, 10.3.2.3,10.3.2.4, 10.3.2.5, 10.3.2.6, 10.3.2.7, 10.3.2.8, 10.3.2.9, 10.3.2.10,10.3.3.1, 10.3.3.2, 10.3.3.3, 10.3.3.4, 10.3.3.5, 10.3.3.6, 10.3.3.7,10.3.3.8, 10.3.3.9, 10.3.3.10, 10.3.4.1, 10.3.4.2, 10.3.4.3, 10.3.4.4,10.3.4.5, 10.3.4.6, 10.3.4.7, 10.3.4.8, 10.3.4.9, 10.3.4.10, 10.3.5.1,10.3.5.2, 10.3.5.3, 10.3.5.4, 10.3.5.5, 10.3.5.6, 10.3.5.7, 10.3.5.8,10.3.5.9, 10.3.5.10, 10.3.6.1, 10.3.6.2, 10.3.6.3, 10.3.6.4, 10.3.6.5,10.3.6.6, 10.3.6.7, 10.3.6.8, 10.3.6.9, 10.3.6.10, 10.3.7.1, 10.3.7.2,10.3.7.3, 10.3.7.4, 10.3.7.5, 10.3.7.6, 10.3.7.7, 10.3.7.8, 10.3.7.9,10.3.7.10, 10.3.8.1, 10.3.8.2, 10.3.8.3, 10.3.8.4, 10.3.8.5, 10.3.8.6,10.3.8.7, 10.3.8.8, 10.3.8.9, 10.3.8.10, 10.3.9.1, 10.3.9.2, 10.3.9.3,10.3.9.4, 10.3.9.5, 10.3.9.6, 10.3.9.7, 10.3.9.8, 10.3.9.9, 10.3.9.10,10.3.10.1, 10.3.10.2, 10.3.10.3, 10.3.10.4, 10.3.10.5, 10.3.10.6,10.3.10.7, 10.3.10.8, 10.3.10.9, 10.3.10.10, 10.4.1.1, 10.4.1.2,10.4.1.3, 10.4.1.4, 10.4.1.5, 10.4.1.6, 10.4.1.7, 10.4.1.8, 10.4.1.9,10.4.1.10, 10.4.2.1, 10.4.2.2, 10.4.2.3, 10.4.2.4, 10.4.2.5, 10.4.2.6,10.4.2.7, 10.4.2.8, 10.4.2.9, 10.4.2.10, 10.4.3.1, 10.4.3.2, 10.4.3.3,10.4.3.4, 10.4.3.5, 10.4.3.6, 10.4.3.7, 10.4.3.8, 10.4.3.9, 10.4.3.10,10.4.4.1, 10.4.4.2, 10.4.4.3, 10.4.4.4, 10.4.4.5, 10.4.4.6, 10.4.4.7,10.4.4.8, 10.4.4.9, 10.4.4.10, 10.4.5.1, 10.4.5.2, 10.4.5.3, 10.4.5.4,10.4.5.5, 10.4.5.6, 10.4.5.7, 10.4.5.8, 10.4.5.9, 10.4.5.10, 10.4.6.1,10.4.6.2, 10.4.6.3, 10.4.6.4, 10.4.6.5, 10.4.6.6, 10.4.6.7, 10.4.6.8,10.4.6.9, 10.4.6.10, 10.4.7.1, 10.4.7.2, 10.4.7.3, 10.4.7.4, 10.4.7.5,10.4.7.6, 10.4.7.7, 10.4.7.8, 10.4.7.9, 10.4.7.10, 10.4.8.1, 10.4.8.2,10.4.8.3, 10.4.8.4, 10.4.8.5, 10.4.8.6, 10.4.8.7, 10.4.8.8, 10.4.8.9,10.4.8.10, 10.4.9.1, 10.4.9.2, 10.4.9.3, 10.4.9.4, 10.4.9.5, 10.4.9.6,10.4.9.7, 10.4.9.8, 10.4.9.9, 10.4.9.10, 10.4.10.1, 10.4.10.2,10.4.10.3, 10.4.10.4, 10.4.10.5, 10.4.10.6, 10.4.10.7, 10.4.10.8,10.4.10.9, 10.4.10.10, 10.5.1.1, 10.5.1.2, 10.5.1.3, 10.5.1.4, 10.5.1.5,10.5.1.6, 10.5.1.7, 10.5.1.8, 10.5.1.9, 10.5.1.10, 10.5.2.1, 10.5.2.2,10.5.2.3, 10.5.2.4, 10.5.2.5, 10.5.2.6, 10.5.2.7, 10.5.2.8, 10.5.2.9,10.5.2.10, 10.5.3.1, 10.5.3.2, 10.5.3.3, 10.5.3.4, 10.5.3.5, 10.5.3.6,10.5.3.7, 10.5.3.8, 10.5.3.9, 10.5.3.10, 10.5.4.1, 10.5.4.2, 10.5.4.3,10.5.4.4, 10.5.4.5, 10.5.4.6, 10.5.4.7, 10.5.4.8, 10.5.4.9, 10.5.4.10,10.5.5.1, 10.5.5.2, 10.5.5.3, 10.5.5.4, 10.5.5.5, 10.5.5.6, 10.5.5.7,10.5.5.8, 10.5.5.9, 10.5.5.10, 10.5.6.1, 10.5.6.2, 10.5.6.3, 10.5.6.4,10.5.6.5, 10.5.6.6, 10.5.6.7, 10.5.6.8, 10.5.6.9, 10.5.6.10, 10.5.7.1,10.5.7.2, 10.5.7.3, 10.5.7.4, 10.5.7.5, 10.5.7.6, 10.5.7.7, 10.5.7.8,10.5.7.9, 10.5.7.10, 10.5.8.1, 10.5.8.2, 10.5.8.3, 10.5.8.4, 10.5.8.5,10.5.8.6, 10.5.8.7, 10.5.8.8, 10.5.8.9, 10.5.8.10, 10.5.9.1, 10.5.9.2,10.5.9.3, 10.5.9.4, 10.5.9.5, 10.5.9.6, 10.5.9.7, 10.5.9.8, 10.5.9.9,10.5.9.10, 10.5.10.1, 10.5.10.2, 10.5.10.3, 10.5.10.4, 10.5.10.5,10.5.10.6, 10.5.10.7, 10.5.10.8, 10.5.10.9, 10.5.10.10, 10.6.1.1,10.6.1.2, 10.6.1.3, 10.6.1.4, 10.6.1.5, 10.6.1.6, 10.6.1.7, 10.6.1.8,10.6.1.9, 10.6.1.10, 10.6.2.1, 10.6.2.2, 10.6.2.3, 10.6.2.4, 10.6.2.5,10.6.2.6, 10.6.2.7, 10.6.2.8, 10.6.2.9, 10.6.2.10, 10.6.3.1, 10.6.3.2,10.6.3.3, 10.6.3.4, 10.6.3.5, 10.6.3.6, 10.6.3.7, 10.6.3.8, 10.6.3.9,10.6.3.10, 10.6.4.1, 10.6.4.2, 10.6.4.3, 10.6.4.4, 10.6.4.5, 10.6.4.6,10.6.4.7, 10.6.4.8, 10.6.4.9, 10.6.4.10, 10.6.5.1, 10.6.5.2, 10.6.5.3,10.6.5.4, 10.6.5.5, 10.6.5.6, 10.6.5.7, 10.6.5.8, 10.6.5.9, 10.6.5.10,10.6.6.1, 10.6.6.2, 10.6.6.3, 10.6.6.4, 10.6.6.5, 10.6.6.6, 10.6.6.7,10.6.6.8, 10.6.6.9, 10.6.6.10, 10.6.7.1, 10.6.7.2, 10.6.7.3, 10.6.7.4,10.6.7.5, 10.6.7.6, 10.6.7.7, 10.6.7.8, 10.6.7.9, 10.6.7.10, 10.6.8.1,10.6.8.2, 10.6.8.3, 10.6.8.4, 10.6.8.5, 10.6.8.6, 10.6.8.7, 10.6.8.8,10.6.8.9, 10.6.8.10, 10.6.9.1, 10.6.9.2, 10.6.9.3, 10.6.9.4, 10.6.9.5,10.6.9.6, 10.6.9.7, 10.6.9.8, 10.6.9.9, 10.6.9.10, 10.6.10.1, 10.6.10.2,10.6.10.3, 10.6.10.4, 10.6.10.5, 10.6.10.6, 10.6.10.7, 10.6.10.8,10.6.10.9, 10.6.10.10, 10.7.1.1, 10.7.1.2, 10.7.1.3, 10.7.1.4, 10.7.1.5,10.7.1.6, 10.7.1.7, 10.7.1.8, 10.7.1.9, 10.7.1.10, 10.7.2.1, 10.7.2.2,10.7.2.3, 10.7.2.4, 10.7.2.5, 10.7.2.6, 10.7.2.7, 10.7.2.8, 10.7.2.9,10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 10.7.3.4, 10.7.3.5, 10.7.3.6,10.7.3.7, 10.7.3.8, 10.7.3.9, 10.7.3.10, 10.7.4.1, 10.7.4.2, 10.7.4.3,10.7.4.4, 10.7.4.5, 10.7.4.6, 10.7.4.7, 10.7.4.8, 10.7.4.9, 10.7.4.10,10.7.5.1, 10.7.5.2, 10.7.5.3, 10.7.5.4, 10.7.5.5, 10.7.5.6, 10.7.5.7,10.7.5.8, 10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4,10.7.6.5, 10.7.6.6, 10.7.6.7, 10.7.6.8, 10.7.6.9, 10.7.6.10, 10.7.7.1,10.7.7.2, 10.7.7.3, 10.7.7.4, 10.7.7.5, 10.7.7.6, 10.7.7.7, 10.7.7.8,10.7.7.9, 10.7.7.10, 10.7.8.1, 10.7.8.2, 10.7.8.3, 10.7.8.4, 10.7.8.5,10.7.8.6, 10.7.8.7, 10.7.8.8, 10.7.8.9, 10.7.8.10, 10.7.9.1, 10.7.9.2,10.7.9.3, 10.7.9.4, 10.7.9.5, 10.7.9.6, 10.7.9.7, 10.7.9.8, 10.7.9.9,10.7.9.10, 10.7.10.1, 10.7.10.2, 10.7.10.3, 10.7.10.4, 10.7.10.5,10.7.10.6, 10.7.10.7, 10.7.10.8, 10.7.10.9, 10.7.10.10, 10.8.1.1,10.8.1.2, 10.8.1.3, 10.8.1.4, 10.8.1.5, 10.8.1.6, 10.8.1.7, 10.8.1.8,10.8.1.9, 10.8.1.10, 10.8.2.1, 10.8.2.2, 10.8.2.3, 10.8.2.4, 10.8.2.5,10.8.2.6, 10.8.2.7, 10.8.2.8, 10.8.2.9, 10.8.2.10, 10.8.3.1, 10.8.3.2,10.8.3.3, 10.8.3.4, 10.8.3.5, 10.8.3.6, 10.8.3.7, 10.8.3.8, 10.8.3.9,10.8.3.10, 10.8.4.1, 10.8.4.2, 10.8.4.3, 10.8.4.4, 10.8.4.5, 10.8.4.6,10.8.4.7, 10.8.4.8, 10.8.4.9, 10.8.4.10, 10.8.5.1, 10.8.5.2, 10.8.5.3,10.8.5.4, 10.8.5.5, 10.8.5.6, 10.8.5.7, 10.8.5.8, 10.8.5.9, 10.8.5.10,10.8.6.1, 10.8.6.2, 10.8.6.3, 10.8.6.4, 10.8.6.5, 10.8.6.6, 10.8.6.7,10.8.6.8, 10.8.6.9, 10.8.6.10, 10.8.7.1, 10.8.7.2, 10.8.7.3, 10.8.7.4,10.8.7.5, 10.8.7.6, 10.8.7.7, 10.8.7.8, 10.8.7.9, 10.8.7.10, 10.8.8.1,10.8.8.2, 10.8.8.3, 10.8.8.4, 10.8.8.5, 10.8.8.6, 10.8.8.7, 10.8.8.8,10.8.8.9, 10.8.8.10, 10.8.9.1, 10.8.9.2, 10.8.9.3, 10.8.9.4, 10.8.9.5,10.8.9.6, 10.8.9.7, 10.8.9.8, 10.8.9.9, 10.8.9.10, 10.8.10.1, 10.8.10.2,10.8.10.3, 10.8.10.4, 10.8.10.5, 10.8.10.6, 10.8.10.7, 10.8.10.8,10.8.10.9, 10.8.10.10, 10.9.1.1, 10.9.1.2, 10.9.1.3, 10.9.1.4, 10.9.1.5,10.9.1.6, 10.9.1.7, 10.9.1.8, 10.9.1.9, 10.9.1.10, 10.9.2.1, 10.9.2.2,10.9.2.3, 10.9.2.4, 10.9.2.5, 10.9.2.6, 10.9.2.7, 10.9.2.8, 10.9.2.9,10.9.2.10, 10.9.3.1, 10.9.3.2, 10.9.3.3, 10.9.3.4, 10.9.3.5, 10.9.3.6,10.9.3.7, 10.9.3.8, 10.9.3.9, 10.9.3.10, 10.9.4.1, 10.9.4.2, 10.9.4.3,10.9.4.4, 10.9.4.5, 10.9.4.6, 10.9.4.7, 10.9.4.8, 10.9.4.9, 10.9.4.10,10.9.5.1, 10.9.5.2, 10.9.5.3, 10.9.5.4, 10.9.5.5, 10.9.5.6, 10.9.5.7,10.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6.1, 10.9.6.2, 10.9.6.3, 10.9.6.4,10.9.6.5, 10.9.6.6, 10.9.6.7, 10.9.6.8, 10.9.6.9, 10.9.6.10, 10.9.7.1,10.9.7.2, 10.9.7.3, 10.9.7.4, 10.9.7.5, 10.9.7.6, 10.9.7.7, 10.9.7.8,10.9.7.9, 10.9.7.10, 10.9.8.1, 10.9.8.2, 10.9.8.3, 10.9.8.4, 10.9.8.5,10.9.8.6, 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1, 10.9.9.2,10.9.9.3, 10.9.9.4, 10.9.9.5, 10.9.9.6, 10.9.9.7, 10.9.9.8, 10.9.9.9,10.9.9.10, 10.9.10.1, 10.9.10.2, 10.9.10.3, 10.9.10.4, 10.9.10.5,10.9.10.6, 10.9.10.7, 10.9.10.8, 10.9.10.9, 10.9.10.10, 10.10.1.1,10.10.1.2, 10.10.1.3, 10.10.1.4, 10.10.1.5, 10.10.1.6, 10.10.1.7,10.10.1.8, 10.10.1.9, 10.10.1.10, 10.10.2.1, 10.10.2.2, 10.10.2.3,10.10.2.4, 10.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9,10.10.2.10, 10.10.3.1, 10.10.3.2, 10.10.3.3, 10.10.3.4, 10.10.3.5,10.10.3.6, 10.10.3.7, 10.10.3.8, 10.10.3.9, 10.10.3.10, 10.10.4.1,10.10.4.2, 10.10.4.3, 10.10.4.4, 10.10.4.5, 10.10.4.6, 10.10.4.7,10.10.4.8, 10.10.4.9, 10.10.4.10, 10.10.5.1, 10.10.5.2, 10.10.5.3,10.10.5.4, 10.10.5.5, 10.10.5.6, 10.10.5.7, 10.10.5.8, 10.10.5.9,10.10.5.10, 10.10.6.1, 10.10.6.2, 10.10.6.3, 10.10.6.4, 10.10.6.5,10.10.6.6, 10.10.6.7, 10.10.6.8, 10.10.6.9, 10.10.6.10, 10.10.7.1,10.10.7.2, 10.10.7.3, 10.10.7.4, 10.10.7.5, 10.10.7.6, 10.10.7.7,10.10.7.8, 10.10.7.9, 10.10.7.10, 10.10.8.1, 10.10.8.2, 10.10.8.3,10.10.8.4, 10.10.8.5, 10.10.8.6, 10.10.8.7, 10.10.8.8, 10.10.8.9,10.10.8.10, 10.10.9.1, 10.10.9.2, 10.10.9.3, 10.10.9.4, 10.10.9.5,10.10.9.6, 10.10.9.7, 10.10.9.8, 10.10.9.9, 10.10.9.10, 10.10.10.1,10.10.10.2, 10.10.10.3, 10.10.10.4, 10.10.10.5, 10.10.10.6, 10.10.10.7,10.10.10.8, 10.10.10.9, 10.10.10.10

Additional exemplary formula B compound groups include the followingcompound groups disclosed below. Unless otherwise specified, theconfigurations of all hydrogen atoms and R groups for the followingcompound groups are as defined for the group 1 compounds of formula Babove. As is apparent from the description, each of the compound groupsdisclose a significant number of unique compounds or generic structures.The compounds or generic structures specifically described in any of thecompound groups are thus exemplary only and the remaining compounds orstructures in each group are described by Tables A and B as noted ineach group.

As used in the description of compounds in the compound groups, thedefinitive structure of compounds in the various compound groups isspecified only by the structure defining portion of the compound groupand in Tables A and B, which together definitively name or specifiesindividual compound or genus structures. The structure defining portionof the compound groups is generally contained in the first sentence thecompound groups below. This applies regardless of any name or structure,including chemical names in the exemplary compounds that are named insome of the compound groups. Thus, any name or structure for anycompound or compound genus that refers to a compound or genus in acompound group and is given anywhere in the disclosure is intended onlyto refer to the compound or genus that is definitively specified by thecompound groups together with Tables A and B.

Group 2. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that R^(10E) is hydrogen in the β-configuration. Asexamples, group 2 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-amino-5β-androstane and compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17β-amino-5β-androstane.

Group 3. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 5-6 position is present.Thus, group 3 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-aminoandrost-5-ene and compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene.

Group 4. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus as described for group 1compounds, except that double bonds at the 1-2- and 5-6 positions arepresent. Thus, group 4 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-aminoandrost-1,5-diene and compound 1.1.4.1is 3β-hydroxy-16α-fluoro-17β-aminoandrost-1,5-diene.

Group 5. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 1-2 position is present.Thus, group 5 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-aminoandrost-1-ene and compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17β-aminoandrost-1-ene.

Group 6. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 1-2 position is present andhydrogen at the 5-position is in the β-configuration. Thus, group 5Acompound 1.2.7.1 is 3β,7β-dihydroxy-16-oxo-17β-amino-5β-androst-1-eneand 5A compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17β-amino-5β-androst-1-ene.

Group 7. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 4-5 position is present.Thus, group 6 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-aminoandrost-4-ene and compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17β-aminoandrost-4-ene.

Group 8. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at both the 1-2 and 4-5 positionsare present. Thus, group 7 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-aminoandrost-1,4-diene and compound 1.1.4.1is 3β-hydroxy-16α-fluoro-17β-aminoandrost-1,4-diene.

Group 9. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 16-17 position is present.For this group and other compound groups that contain a 16-17 doublebond, the R³ and R⁴ moieties will only be single bonded. Moieties suchas ═O are thus not included as R³ or R⁴ substituents in the compoundgroup, since this would give rise to a pentavalent carbon at the 16- or17-position. Thus, group 8 compound 1.2.7.1 does not represent anycompound since a 16-17 double bond and an ═O at 16 can not both bepresent at the same time, while group 8 compound 1.1.4.1 is3β-hydroxy-16-fluoro-17-aminoandrost-16-ene.

Group 10. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 16-17 position is presentand hydrogen at the 5-position is in the β-configuration. Thus, group 8Acompound 1.2.7.1 is 3β,7β-dihydroxy-16-oxo-17β-amino-5β-androst-16-eneand 8A compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17β-amino-5β-androst-16-ene.

Group 11. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 16-17 and 5-6 positions arepresent. Thus, group 9 compound 1.1.4.1 is3β-hydroxy-16-fluoro-17-aminoandrost-5,16-diene.

Group 12. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 16-17 and 1-2 positions arepresent. Thus, group 10 compound 1.1.4.1 is3β-hydroxy-16-fluoro-17-aminoandrost-1,16-diene.

Group 13. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 16-17 and 1-2 positions arepresent and hydrogen at the 5-position is in the β-configuration. Thus,group 10A compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-amino-5β-androst-1,16-diene and 10A compound1.1.4.1 is 3β-hydroxy-16α-fluoro-17β-amino-5β-androst-1,16-diene.

Group 14. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 16-17 and 4-5 positions arepresent. Thus, group 11 compound 1.1.4.1 is3β-hydroxy-16-fluoro-17-aminoandrost-4,16-diene.

Group 15. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 1-2, 16-17 and 4-5 positionsare present. Thus, group 12 compound 1.1.4.1 is3β-hydroxy-16-fluoro-17-aminoandrost-1,4,16-triene.

Group 16. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 1-2, 16-17 and 5-6 positionsare present. Thus, group 12 compound 1.1.4.1 is3β-hydroxy-16-fluoro-17-aminoandrost-1,5,16-triene.

Group 17. This group contains compounds from groups 1-13 above wherein,for single bonded R¹, R², R³ and R⁴ moieties, R¹, R², R³ and R⁴respectively are in the α,β,β,β, β,β,α,α, β,α,α,β, α,α,α,β, β,β,β,β,β,β,β,α, α, β,β,β, β,α,α,α, β,α, β,β, α,α,α,α, β,α, β,α, α,β,β,α,α,α,β,α, α,β,α,α or α,α,β,β configurations. Thus, when R¹, R², R³ and R⁴respectively are in the α,β,α,β configurations, group 14 compound1.2.7.1 from group 3 (also referred to as group 14-3 compound 1.2.7.1)is 3α,7β-dihydroxy-16-oxo-17β-aminoandrost-5-ene and compound 1.1.4.1from group 3 (also referred to as group 14-3 compound 1.1.4.1) is3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene. When R¹, R², R³ and R⁴respectively are in the α,β,α,β configurations, group 14 compound1.2.7.1 from group 1 (also referred to as group 14-1 compound 1.2.7.1)is 3α,7β-dihydroxy-16-oxo-17β-aminoandrostane and group 14-1 compound1.1.4.1 is 3α-hydroxy-16α-fluoro-17β-aminoandrostane. Similarly, whenR¹, R², R³ and R⁴ respectively are in the α,β,α,β configurations, group14-6 compound 1.2.7.1 is 3α,7β-dihydroxy-16-oxo-17βaminoandrost-4-eneand group 14-6 compound 1.1.4.1 is3α-hydroxy-16α-fluoro-17β-aminoandrost-4-ene.

Group 18. This group contains compounds in groups 1-14 above whereinR^(10F), R^(10G) and R^(10H) respectively are in the β,α,β, β,β,α,α,β,β, β,β,β, α,α,α, α,β,α or α,α,β configurations. Thus, when R^(10F),R^(10G) and R^(10H) respectively are in the β,α,β configurations, group15 compound 1.2.7.1 from group 3 is3β,7β-dihydroxy-16-oxo-17β-amino-14β-androst-5-ene and compound 1.1.4.1from group 3 is 3β-hydroxy-16α-fluoro-17β-amino-14β-androst-5-ene. WhenR^(10E), R^(10F), R^(10G) and R^(10H) respectively are in the α,β,α,βconfigurations, group 15 compound 1.2.7.1 from group 1 is3α,7β-dihydroxy-16-oxo-17β-amino-14β-androstane and compound 1.1.4.1from group 1 is 3α-hydroxy-16α-fluoro-17β-amino-14β-androstane. WhenR^(10F), R^(10G) and R^(10H) respectively are in the β,α,βconfigurations and R¹, R², R³ and R⁴ respectively are in the α,β,α,βconfigurations as included in group 14, group 15-14-3 compound 1.2.7.1(compound 1.2.7.1 from groups 14 and 3) is3α,7β-dihydroxy-16-oxo-17β-amino-14β-androst-5-ene and group 15-14-3compound 1.1.4.1 is 3α-hydroxy-16α-fluoro-17β-amino-14β-androst-5-ene.When R^(10G) is —F in the α-configuration and R^(10F) and R^(10H) are —Hin the β- and α-configurations respectively, group 15-3 compound 1.1.4.1is 3β-hydroxy-9α,16α-difluoro-17β-aminoandrost-5-ene and 15-3 compound1.1.5.1 is 3β-hydroxy-9α-fluoro-17β-aminoandrost-5-ene.

Group 19. This group contains compounds in groups 1-15 above wherein 1or 2 of R^(10A), R^(10B), R^(10C) and R^(10D) are not —H and are anindependently chosen moiety as defined herein, e.g., optionallysubstituted alkyl, —CH₃, halogen, —SR^(PR) or —OR^(PR), wherein eachR^(10A), R^(10B), R^(10C) and R^(10D) is independently in theα-configuration or the β-configuration and R^(PR) independently are —Hor a protecting group. Thus, when R^(10C) and R^(10H) are both not —H,they can be in the β,β,β,α, α,β or α,α configurations respectively.Similarly, when R^(10B) and R^(10D) are both not —H, they can be in theβ,β,β,α, α,β or α,α configurations respectively, or, when R^(10B) is not—H and R^(10A), R^(10C) and R^(10D) are all —H, R^(10B) can be in theα-configuration or the β-configuration. Thus, when R^(10C) is —Cl in theα-configuration, group 16-3 compound 1.2.7.1 is3β,7β-dihydroxy-6-chloro-16-oxo-17β-aminoandrost-5-ene and group 16-3compound 1.1.4.1 is3β-hydroxy-6-chloro-16α-fluoro-17β-aminoandrost-5-ene. When R^(10C) is—Br in the α-configuration, group 16-1 compound 1.2.7.1 is3β,7β-dihydroxy-6α-bromo-16-oxo-17β-aminoandrostane and group 16-1compound 1.1.4.1 is 3β-hydroxy-6α-bromo-16α-fluoro-17β-aminoandrostane.

Group 20. This group contains compounds in groups 1-16 above wherein (1)one or both of R⁵ and R⁶ are not —CH₃ and they independently are amoiety as defined herein, and (2) R⁵ and R⁶ are in the β,β,βα, α,β orα,α configurations respectively. Thus, R⁵ and R⁶ independently can be—H, —CH₃, —C₂H₅, —C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br,—I or another single bonded moiety as defined herein in the β,β,β,α, α,βor α,α configurations. When, for example, R⁵ is —CH₃, R⁶ is —H and bothare in the β-configuration, group 17-1 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-amino-19-norandrostane and group 17-1compound 1.1.4.1 is 3β-hydroxy-16α-fluoro-17β-amino-19-norandrostane.When R⁵ is —CH₃, R⁶ is —H and both are in the β-configuration, group17-3 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-amino-19-norandrost-5-ene and group 17-3compound 1.1.4.1 is 3β-hydroxy-16α-fluoro-17β-amino-19-norandrost-5-ene.When R⁵ is —CH₃, R⁶ is —H and both are in the β-configuration, R^(10G)is —F in the α-configuration and R^(10F) and R^(10H) are —H in the β-and α-configurations respectively, group 17-15-3 compound 1.1.4.1 is3β-hydroxy-9α,16α-difluoro-17β-amino-19-norandrost-5-ene and 17-15-3compound 1.1.5.1 is 3β-hydroxy-9α-fluoro-17β-amino-19-norandrost-5-ene.

Group 21. This group contains compounds in groups 1-17 above wherein R⁷is not —CH₂— and is another R⁷ moiety defined herein, e.g., —O—, —NH—,—S—, —CH₂—CH₂— or —C(R¹⁰)₂— where each R¹⁰ is an independently chosenmoiety described herein. Exemplary R⁷ include —C(halogen)₂- such as—CF₂—, —CH(α-optionally substituted alkyl), —CH(β-optionally substitutedalkyl), —CH(α-OH), —CH(β-OH) or —C(optionally substituted alkyl)₂- suchas —C(CH₃)₂— or —C(C₂H₅)(CH₃)—. Each optionally substituted alkyl groupcan contain 1, 2, 3, 4, 5, 6, 7, 8 or more carbon atoms as definedpreviously.

Group 22. This group contains compounds in groups 1-18 above wherein R⁸is not —CH₂— and is another R⁸ moiety defined herein, e.g., —O—, —NH—,—S— or —C(R¹⁰)₂— where each R¹⁰ is an independently chosen moietydescribed herein. Exemplary R⁸ include —C(halogen)₂- such as —CF₂—,—CH(α-optionally substituted alkyl), —CH(β-optionally substituted alkyl)or —C(optionally substituted alkyl)₂- such as —C(CH₃)₂— or—C(C₂H₅)(CH₃)—. Each optionally substituted alkyl group can contain 1,2, 3, 4, 5, 6, 7, 8 or more carbon atoms as defined previously. In someembodiments, when one or both R¹⁰ at R⁸ is —OH, —SH, ═O, an ester, athioester, or another moiety that can give rise to a hydroxyl group bymetabolism or hydrolysis, R² and/or R^(10D) is not —H. As examples,group 19-3 compound 1.1.4.1 is3β-hydroxy-11-oxa-16α-fluoro-17β-aminoandrost-5-ene and 19-3 compound1.1.5.1 is 3β-hydroxy-11-oxa-17β-aminoandrost-5-ene. When R⁸ is —O—, R⁵is —CH₃, R⁶ is —H and both are in the β-configuration, R^(10G) is —F inthe α-configuration and R^(10F) and R^(10H) are —H in the β- andα-configurations respectively, group 19-17-15-3 compound 1.1.4.1 is3β-hydroxy-9α,16α-difluoro-11-oxa-17β-amino-19-norandrost-5-ene and19-17-15-3 compound 1.1.5.1 is3β-hydroxy-9α-fluoro-11-oxa-17β-amino-19-norandrost-5-ene.

Group 23. This group contains compounds in groups 1-19 above wherein R⁹is not —CH₂— and is another R⁹ moiety defined herein, e.g., —O—, —NH—,—S— or —C(R¹⁰)₂— where each R¹⁰ is an independently chosen moiety asdefined herein. Exemplary R⁹ include —C(halogen)₂- such as —CF₂—,—CH(α-OH), —CH(β-OH) or —C(optionally substituted alkyl)₂-such as—O(CH₃)₂— or —C(C₂H₅)(CH₃)—. Each optionally substituted alkyl group cancontain 1, 2, 3, 4, 5, 6, 7, 8 or more carbon atoms as definedpreviously. For groups that contain a double bond at the 1-2 positionsuch as groups 5 and 7, R⁹ can be —N═, but R⁹ will not be —O— or —S— dueto improper bonding, i.e., —O═ and —S═ are not present in the steroidring.

Group 24. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1—optionally substituted amine, 2—optionally substituted amide,3—optionally substituted oxime, 4—optionally substituted alkyl,5—optionally substituted alkenyl, 6—optionally substituted alkynyl,7—optionally substituted aryl, 8—optionally substituted heterocycle,9—ether, e.g., methoxy, ethoxy or methoxymethyl and 10—ester, e.g.,acetate, propionate, enanthate or trifluoroacetate. Any of these groupscan be a moiety defined herein for that group. Thus, for Table Asubstituent 1, optionally substituted amine, the R⁴ group includesmoieties such as —NH₃ ⁺Cl⁻, —NH₃ ⁺Br⁻, —NH₃ ⁺I⁻, optionally substitutedalkylamine, di-optionally substituted alkylamine, —NHR^(PR), —N(R^(PR))₂and —NH—CH₃, where R^(PR) are a protecting group. Similarly, optionallysubstituted amide includes moieties such as —C(O)—NH₂, —C(O)—NH—C(CH₃)₃and —C(O)—NH₂, which are described herein. Other R⁴ moieties include═N—OCH₃, ═N—OC₂H₅, ═N—OC₃H₇ and ═N—O-optionally substituted alkyl. Group21-3 compound 1.1.6.1 (i.e., group 21 compound 1.1.6.1 from group 3) is3β,16α-dihydroxy-17β-optionally substituted amine-androst-5-ene and 21-3compound 1.1.4.1 is 3β-hydroxy-16α-fluoro-17β-optionally substitutedamine-androst-5-ene, where the optionally substituted amine is a moietydescribed herein such as an amine salt, an optionally substitutedalkylamine or an optionally substituted dialkylamine like —NH₃ ⁺Cl⁻,—NHCH₃, —N(CH₃)₂ and —NH—(CH₂)₂—OH. Similarly, group 21-1 compound1.1.6.1 (i.e., group 21 compound 1.1.6.1 from group 1) is3β,16α-dihydroxy-17β-optionally substituted amine-androstane and 21-1compound 1.1.4.1 is 3β-hydroxy-16α-fluoro-17β-optionally substitutedamine-androstane.

Group 25. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1—phosphate thioether, 2—thionoester, 3—amino acid, 4—peptide,5—dipeptide, 6—optionally substituted heterocycle, 7—optionallysubstituted carboxyl, 8—carbonate, 9—carbamate and 10—phosphothioester.Amino acids for substituent 3 are as described herein and include, e.g.,—NH—CH₂—C(O)OH, —NH—CH₂—C(O)OR^(PR), —NH—CH₂—CH₂—C(O)OH,—NH—CH₂—CH₂—C(O)OR^(PR), —NH—CH(CH₃)—C(O)OH, —NH—CH(CH₃)—CH₂—C(O)OH,—NH—CH(CH₃)—CH₂—C(O)OR^(PR), —NH—CH₂—CH₂—CH₂—C(O)OH,—NH—CH₂—CH₂—CH₂—C(O)OR^(PR), —O—C(O)—CH₂—NH₂, —O—C(O)—CH₂—NHR^(PR),—O—C(O)—CH₂—CH₂—NH₂, —O—C(O)—CH₂—CH₂—NHR^(PR) or for ionizable groupssuch as free carboxyls or amines, a salt such as a Na⁺ or K⁺ salt forcarboxyls or a salt such as HCl or HBr salt for amines.

Group 26. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-pyrrolidine, 2 —N1-pyrazolone, 3 —N2-pyrazolone, 4—N-imidazolidin-2-one, 5 —N1-imidazole, 6 —N1-4,5-dihydroimidazole, 7—N-morpholine, 8 —N1-pyridine, 9 —N-piperidine, 10 —N-piperazine. Asexamples, group 26A-3 compound 1.1.6.1 (i.e., group 26A compound 1.1.6.1from group 3) is 3β,16α-dihydroxy-17β-N-pyrrolidinylandrost-5-ene, 26A-3compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17β-N-pyrrolidinylandrost-5-ene, group 26A-4compound 1.1.6.1 (i.e., group 26A compound 1.1.6.1 from group 4) is3β,16α-dihydroxy-17β-N-pyrrolidinylandrost-1,5-diene and 26A-4 compound1.1.4.1 is 3β-hydroxy-16α-fluoro-17β-N-pyrrolidinylandrost-1,5-diene.

Group 27. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-piperazine substituted at N4 with optionally substitutedalkyl, 2 —N-indole, 3 —N-indoline, 4 —N-quinolidine, 5—NH—C(O)—CH₂—CH₂—C(O)—OH, 6 —NH—C(O)—CH₂—C(O)—OH, 7—NH—C(O)—CH₂—CH₂—C(O)—OR^(PR), 8 —NH—C(O)—CH₂—C(O)—OR^(PR), 9—NH—C(O)—(CH₂)₃—C(O)—OH, 10 —NH—C(O)—(CH₂)₃—C(O)—OR^(PR). Ionizablemoieties such as free carboxyl groups include salts, e.g., Na⁺ or K⁺.R^(PR) is a protecting group.

Group 28. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1—optionally substituted amine, 2—optionally substituted amide,3—optionally substituted oxime, 4—optionally substituted alkyl,5—optionally substituted alkenyl, 6—optionally substituted alkynyl,7—optionally substituted aryl, 8—optionally substituted heterocycle,9—ether and 10—ester. Any of these groups can be a moiety defined hereinfor that group.

Group 29. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1—phosphate thioether, 2—thionoester, 3—amino acid, 4—peptide,5—dipeptide, 6—optionally substituted heterocycle, 7—optionallysubstituted carboxyl, 8—carbonate, 9—carbamate and 10—phosphothioester.

Group 30. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-pyrrolidine, 2 —N1-pyrazolone, 3 —N2-pyrazolone, 4—N-imidazolidin-2-one, 5 —N1-imidazole, 6 —N1-4,5-dihydroimidazole, 7—N-morpholine, 8 —N1-pyridine, 9 —N-piperidine, 10 —N-piperazine.

Group 31. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-piperazine substituted at N4 with optionally substitutedalkyl, 2 —N-indole, 3 —N-indoline, 4 —N-quinolidine, 5—NH—C(O)—CH₂—CH₂—C(O)—OH, 6 —NH—C(O)—CH₂—C(O)—OH, 7—NH—C(O)—CH₂—CH₂—C(O)—OR^(PR), 8 —NH—C(O)—CH₂—C(O)—OR^(PR), 9—NH—C(O)—(CH₂)₃—C(O)—OH, 10 —NH—C(O)—(CH₂)₃—C(O)—OR^(PR). Ionizablemoieties such as free carboxyl groups include salts, e.g., Na⁺ or K⁺.R^(PR) is a protecting group.

Group 32. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1—optionally substituted amine, 2—optionally substituted amide,3—optionally substituted oxime, 4—optionally substituted alkyl,5—optionally substituted alkenyl, 6—optionally substituted alkynyl,7—optionally substituted aryl, 8—optionally substituted heterocycle,9—ether and 10—ester. Any of these groups can be a moiety defined hereinfor that group.

Group 33. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1—phosphate thioether, 2—thionoester, 3—amino acid, 4—peptide,5—dipeptide, 6—optionally substituted heterocycle, 7—optionallysubstituted carboxyl, 8—carbonate, 9—carbamate and 10—phosphothioester.

Group 34. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-pyrrolidine, 2 —N1-pyrazolone, 3 —N2-pyrazolone, 4—N-imidazolidin-2-one, 5 —N1-imidazole, 6 —N1-4,5-dihydroimidazole, 7—N-morpholine, 8 —N1-pyridine, 9 —N-piperidine, 10 —N-piperazine.

Group 35. This group contains compounds in groups 1-48 above wherein R⁴is single bonded and a second R⁴ that is not —H is present. The secondR⁴ can be a moiety defined herein for R⁴, e.g., optionally substitutedalkyl, halogen, —SH or —OH.

Group 36. This group contains compounds in groups 1-49 above wherein R¹is single bonded and a second R¹ that is not —H is present. The secondR¹ can be a moiety defined herein for R¹, e.g., optionally substitutedalkyl, halogen, —SH or —OH.

Group 37. This group contains compounds in groups 1-50 above wherein R³is single bonded and a second R³ that is not —H is present. The secondR³ can be a moiety defined herein for R³, e.g., optionally substitutedalkyl, halogen, —SH or —OH.

Group 38. This group contains compounds in groups 1-51 above wherein R²is single bonded and a second R² that is not —H is present. The secondR² can be a moiety defined herein for R², e.g., optionally substitutedalkyl, halogen, —SH or —OH.

Analytical characterization and reference standards. Individual F1Csdescribed or disclosed herein are suitable for use as standards fordetermining chemical or physical properties using one, two or moreanalytical methods, e.g., for use in HPLC, reverse phase HPLC, MS (massspectrometry), quadrupole MS, GC-MS, LC-MS, NMR (nuclear magneticresonance spectrometry), ²H-NMR, ³H-NMR, ¹³C-NMR, ¹⁴C-NMR, infraredspectrometry (IR), Fourier transform-IR, optical rotary dispersion, losson drying for water and solvent measurement, Karl Fisher titration forwater determination, differential scanning calorimetry, melting point,density, refractive index, solubility characteristics in organicsolvents, aqueous systems or aqueous-organic solvent mixtures, thepartition coefficient in immiscible solvent systems, e.g., octanol:waterpartition coefficient, heat stability or epimerization rate orcharacteristics of a given enantiomer. These analytical or chemicalproperties of each F1C are collectively referred to as analyticalcharacteristics. For general methods, see, e.g., H. L. J. Makin et al.,eds. Steroid Analysis 1995, Chapman & Hall, ISBN 0751401285. Thus, toaid in the determination of, e.g., the structure of a metabolite of aF1C or a structurally related compound, the parent compound or anotherstructurally related F1C could be used as a standard. Metabolism of F1Cswill often include one or more of oxidation, reduction, hydroxylation orconjugation, e.g., oxidation or reduction to a —OH or ═O moiety, orconjugation with a moiety such as sulfate, phosphate, amino acid,dipeptide or a monosaccharide such as glucuronic acid at, e.g., the 2,3, 6, 7, 11, 15, 16, 17 or other positions on the steroid nucleus. Inthese embodiments, the appropriate use of a F1C of known structure as astandard can aid in or verify the identification of metabolites that areprojected to have closely related structures. Information regarding theidentification can be useful or sometimes is necessary for, e.g.,obtaining regulatory approval to market a therapeutic agent such as aF1C or understanding the potential biological role that a F1C or itsmetabolite can play in one of the applications disclosed herein or in acited reference.

Embodiments include a method (the “characterization method”) tocharacterize or at least partially characterize a formula 1 compoundthat is at least partially uncharacterized for one or more givenchemical or analytical properties, e.g., a known or potential metaboliteof a parent formula 1 compound, comprising (a) providing a formula 1compound having one, two or more known characteristics, e.g., a known orat least partially known or characterized chemical structure, XRDspectrum or melting point (a “CF1C”), and a formula 1 compound that isunknown or at least partially uncharacterized, i.e., is uncharacerizedfor at least one of the same analytical characteristics (a “UCF1C”), (b)obtaining one, two or more analytical characteristics of the UCF1C, and(c) comparing the 1, 2 or more analytical characteristics of the CF1Cwith the analytical characteristics of the UCF1C. The steps in thismethod may be conducted in any suitable order, e.g., analytical orchemical data for the CF1C will usually be obtained before or at aboutthe same time as one obtains the analytical or chemical data for theUCF1C. Usually the CF1C will be more completely characterized than theUCF1C, particularly with regard to its chemical structure or itsrelative degree of purity or with regard to the analytical or chemicaldata that is being sought. This method allows further characterizationof the UCF1C, e.g., by confirming the UCF1C's chemical structure or bydetermining the UCF1C's stability under various storage or temperatureconditions or in various formulations or by determining other analyticalor chemical properties of interest. In this method, the CF1C itself maynot be completely characterized, however, for the one, two or moreanalytical characteristics of interest, the CF1C will usually have aknown or confirmed property or properties, while the UCF1C is unknown orat least unconfirmed for the same property or properties.

In some embodiments the characterization method is conducted bycomparing dissimilar analytical characteristics. For example, the CF1Cmay be well characterized by GC-MS or by NMR, while an insufficientamount of the UCF1C is available for analysis with the same technique.In these cases, one can then, e.g., compare the GC-MS of the CF1C withthe NMR of the UCF1C to obtain the same or essentially the sameinformation for the UCF1C. Other examples of where this can be done iswhere DSC data is available for the CF1C, and only melting point data isavailable for the UCF1C. In this case, the CF1C DSC data is compared tothe UCF1C's melting point data. Also, in conducting the characterizationmethod, one can optionally derivatize or chemically modify the CF1Cand/or the UCF1C to facilitate analysis of the compound(s). For example,in conducting MS, GC-MS or NMR analysis, one or more free hydroxyl orketone moieties on the CF1C and/or the F2C can be silylated using, e.g.,trimethylsilyl chloride, t-butyl-dimethylsilyl chloride or othersuitable silylating agents. Similarly, the UCF1C may be treated orincubated with a cell line or tissue or with a glucuronidase, sulfatase,phosphatase, esterase, lipase, oxidoreductase or other enzyme and thencharacterized. This treatment may in some cases convert the UCF1C intothe CF1C, but this conversion would usually be confirmed by one, two ormore suitable analytical methods. Such treatments will usually generateadditional data about the structure, properties or origin of the UCF1C.

Embodiments include modifications of the characterization method thatuse a CF1C and a second formula 1 compound that is believed or known tohave a related structure or empirical formula. In these modifications,the CF1C is used as described and a second formula 1 compound or a UCF1Cthat is believed or known to be, e.g., an epimer or a salt, of the CF1Cis compared to the CF1C. Invention embodiments include othermodifications of the characterization method such as (1) comparinganalytical or chemical data from a single CF1C with 2, 3, 4 or moreUCF1C, (2) comparing analytical or chemical data from 2, 3, 4 or moreCF1C with a single UCF1C and (3) comparing analytical or chemical datafrom 2, 3, 4 or more CF1C with 2, 3, 4 or more UCF1C. In thesemodifications, the CF1C or UCF1C are used essentially as described forthe characterization method, except that data is obtained for the addedformula 1 compounds.

Typically, when the 1, 2 or more analytical characteristics of a CF1C ora UCF1C are obtained, which may be for use in the characterizationmethod or for other purposes, each compound is analyzed under the sameor essentially the same analytical conditions using the same oressentially the same analytical technique or instrument. Variations inan analytical technique may be used where the properties of a CF1C or aUCF1C require slightly different handling or specimen preparation. Anexample of a variation in analytical conditions is the comparison of aproperty of a CF1C, e.g., its stability to heat, humidity or prolongedstorage at a given temperature, with the same property of the CF1C in acomposition containing an excipient(s) or in a formulation (where theCF1C in a composition is then considered the UCF1C for thecharacterization method). This allows the determination of the stabilityof the CF1C as a pure compound compared to its stability in any desiredcomposition.

When characterizing a CF1C by MS, particularly by GC-MS, one willusually conduct an initial characterization of a formula 1 compound or aCF1C in the characterization method using a known GC-MS method (e.g., H.L. J. Makin et al., Mass Spectra and GC Data of Steroids: Androgens andEstrogens 1999 John Wiley & Sons, pages XIII-XIV) or a suitablevariation of this method. For F1Cs that contain free hydroxyls or oxogroups, the hydroxyl groups can be derivatized to an ester such asacetate, hydroxyl and oxo or groups can be derivatized to trimethylsilylether, i.e., —O—Si(CH₃)₃, and oxo groups can be derivatized to a anoxime such as ═N—O—CH₃ before GC-MS analysis. Other functional groupscan also be suitably derivatized. For embodiments of thecharacterization method that use a GC-MS analysis method, the CF1C orthe UCF1C is analyzed by the GC-MS method or a suitable variation toobtain or to confirm chemical structure information about the CF1C orthe UCF1C. Suitable variations include, e.g., a change in the carriergas from helium to hydrogen to increase the sensitivity of detection ora decrease in the ionization from 70 eV to 50 eV can give a betterparent mass ion.

As is apparent from the present disclosure, the F1C may be preparedsynthetically and typical embodiments will utilize purified a F1C.Purified F1C can be free, essentially free or partially free, of otherF1C or other compounds such as excipients. Thus, any given purified F1Ccan be present as a solid that contains, e.g., less than about 15% w/wor less than about 10% w/w or less than about 8% w/w or less than about5% w/w or less than about 3% w/w or less than about 1% w/w of one, twoor more other F1Cs, excipients, synthetic by-products, decompositionproducts or synthesis or purification reactants or reagents. Similarly,the F1C can be present in a solution or suspension that contains atleast about 90% w/w or at least about 95% w/w or at least about 97% w/wof the F1C and one or more excipients and less than about 10% or 8% or5% or 3% w/w or 1% w/w of one, two or more other F1Cs, excipients,synthetic by-products, decomposition products or synthesis orpurification reactants or reagents.

Various groups that F1Cs contain as described herein, e.g., hydroxylgroups or ketones bonded to the steroid nucleus, or substituted alkylgroups, substituted heterocycles, amino acids and peptides, which cancontain one or more reactive moieties such as hydroxyl, oxo, carboxyl,amino or thiol moieties. Intermediates used to make F1Cs may beprotected as is apparent in the art, e.g., using suitable R^(PR)moieties. Noncyclic and cyclic protecting groups and correspondingcleavage reactions are described in “Protective Groups in OrganicChemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991,ISBN 0-471-62301-6) (hereafter “Greene”) and will not be detailed here.In the context of the present invention, these protecting groups aregroups that can be removed from a F1C without irreversibly changing thecovalent bond structure or oxidation/reduction state of the remainder ofthe molecule. For example, the protecting group, —R^(PR), that is bondedto an —OR^(PR) or —NHR^(PR) group can be removed to form —OH or —NH₂,respectively, without affecting other covalent bonds in the molecule.Protecting groups for carbonyl or ketone moieties include ethyleneketals, e.g., —O—CH₂—CH₂—O—. At times, when desired, more than oneprotecting group can be removed at a time, or they can be removedsequentially. In F1Cs containing more than one protecting group, theprotecting groups are the same or different.

Protecting groups are removed by known procedures, although it will beunderstood that the protected intermediates fall within the scope ofthis invention. The removal of the protecting group may be arduous orstraightforward, depending upon the economics and nature of theconversions involved. In general, one will use a protecting group withexocyclic amines or with carboxyl groups during synthesis of a F1C. Formost therapeutic applications amine groups should be deprotected.Protecting groups commonly are employed to protect against covalentmodification of a sensitive group in reactions such as alkylation oracylation. Ordinarily, protecting groups are removed by, e.g.hydrolysis, elimination or aminolysis. Thus, simple functionalconsiderations will suffice to guide the selection of a reversible or anirreversible protecting group at a given locus on the F1Cs. Suitableprotecting groups and criteria for their selection are described in T.W. Greene and P. G. M. Wuts, Eds. “Protective Groups in OrganicSynthesis” 2nd edition, Wiley Press, at pps. 10-142, 143-174, 175-223,224-276, 277-308, 309-405 and 406-454.

Characterization of a protecting group is made in the conventionalmanner, e.g., as described by Kocienski, Philip J.; “Protecting Groups”(Georg Thieme Verlag Stuttgart, New York, 1994) (hereafter “Kocienski”),Section 1.1, page 2, and Greene Chapter 1, pages 1-9. In particular, agroup is a protecting group if when, based on mole ratio, 90% of thatprotecting group has been removed by a deprotection reaction, no morethan 50%, typically 25%, more typically 10%, of the deprotected productmolecules have undergone changes to their covalent bond structure oroxidation/reduction state other than those occasioned by the removal ofthe protecting group. When multiple protecting groups of the same typeare present in the molecule, the mole ratios are determined when all ofthe groups of that type are removed. When multiple protecting groups ofdifferent types are present in the molecule, each type of protectinggroup is treated (and the mole ratios are determined) independently ortogether with others depending on whether the deprotection reactionconditions pertinent to one type are also pertinent to the other typespresent. In one embodiment, a group is a protecting group if when, basedon mole ratio determined by conventional techniques, 90% of thatprotecting group has been removed by a conventional deprotectionreaction, no more than 50%, typically 25%, more typically 10%, of thedeprotected product molecules have undergone irreversible changes totheir covalent bond structure or oxidation/reduction state other thanthose occasioned by the removal of the protecting group. Irreversiblechanges require chemical reactions (beyond those resulting from aqueoushydrolysis, acid/base neutralization or conventional separation,isolation or purification) to restore the covalent bond structure oroxidation/reduction state of the deprotected F1C.

Protecting groups are also described in detail together with generalconcepts and specific strategies for their use in Kocienski, Philip J.;“Protecting Groups” (Georg Thieme Verlag Stuttgart, New York, 1994),which is incorporated by reference in its entirety herein. In particularChapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2,Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol ProtectingGroups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184, Chapter6, Amino Protecting Groups, pages 185-243, Chapter 7, Epilog, pages244-252, and Index, pages 253-260, are incorporated with specificity inthe context of their contents. More particularly, Sections 2.3 SilylEthers, 2.4 Alkyl Ethers, 2.5 Alkoxyalkyl Ethers (Acetals), 2.6 Reviews(hydroxy and thiol protecting groups), 3.2 Acetals, 3.3 SilyleneDerivatives, 3.4 1,1,3,3-Tetraisopropyldisiloxanylidene Derivatives, 3.5Reviews (diol protecting groups), 4.2 Esters, 4.32,6,7-Trioxabicyclo[2.2.2]octanes [OBO] and Other Ortho Esters, 4.4Oxazolines, 4.5 Reviews (carboxyl protecting groups), 5.2 O,O-Acetals,5.3 S,S-Acetals, 5.4 O,S-Acetals, 5.5 Reviews (carbonyl protectinggroups), 6.2 N-Acyl Derivatives, 6.3 N-Sulfonyl Derivatives, 6.4N-Sulfenyl Derivatives, 6.5 N-Alkyl Derivatives, 6.6 N-SilylDerivatives, 6.7 Imine Derivatives, and 6.8 Reviews (amino protectinggroups), are each incorporated with specificity whereprotection/deprotection of the requisite functionalities is discussed.Further still, the tables “Index to the Principal Protecting Groups”appearing on the inside front cover and facing page, “Abbreviations” atpage xiv, and “reagents and Solvents” at page xv are each incorporatedin their entirety herein at this location.

Groups capable of biological cleavage typically include prodrugs. Someexemplary groups are described in “Design of Prodrugs”, Hans Bundgaard(Elsevier, N.Y., 1985, ISBN 0-444-80675-X) (Bundgaard) and will not bedetailed here. In particular, Bundgaard, at pages 1-92, describesprodrugs and their biological cleavage reactions for a number offunctional group types. Prodrugs for carboxyl and hydroxyl groups aredetailed in Bundgaard at pages 3 to 10, for amides, imides and otherNH-acidic compounds at pages 10 to 27, amines at pages 27 to 43, andcyclic prodrugs at pages 62 to 70. These moieties are optionally bondedto the steroid at one, two or more of the variable groups that arebonded to the rings in the F1Cs, e.g., one or more R¹-R⁶, R¹⁰, R¹⁵, R¹⁷and R¹⁸.

In some embodiments one or more F1Cs or groups of F1Cs may be excludedfrom one or more of the uses disclosed herein. For example, if thesubject has or is susceptible to developing a memory impairingneurological disorder or memory impairment condition, excluded compoundscan include 5-androstene-3β-ol-7,17-dione or5-androstene-3β,7-diol-17-one or a derivative of these compounds thatcan has a group at the 7-position that can convert to —OH or ═O byhydrolysis. In other cases, the F1Cs can exclude one or more of4-pregnene-11β,17α,21-triol-3,20-dione,17α,21-dihydroxypregn-4-ene-3,11,20-trione,11β,21-dihydroxy-3,20-dioxopregn-4-en-18-al,11β,17α,21-trihydroxypregna-1,4-diene-3,20-dione,17α,21-dihydroxypregna-1,4-diene-3,11,20-trione,3β-hydroxypregn-5-ene-20-one, 3β-hydroxyandrost-5-ene-17-one,pregn-4-ene-3,20-dione, 21-hydroxypregn-4-ene-3,20-dione,9-fluoro-11β,16α,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione,9-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione,9-fluoro-11β,17α,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione,dehydroepiandrosterone-3-sulfate,1,4-pregnadiene-17α,21-diol-3,11,20-trione, androsterone, androsteroneacetate, androsterone propionate, androsterone benzoate,androst-5-ene-3β,17β-diol, androst-5-ene-3β,17β-diol-3-acetate,androst-5-ene-3β,17β-diol-17-acetate,androst-5-ene-3β,17β-diol-3,17-diacetate,androst-5-ene-3β,17β-diol-17-benzoate,androst-5-ene-3β,17β-diol-3-acetate-17-benzoate,androst-4-ene-3,17-dione, androst-5-ene-3β,7β,17β-triol,androst-5-ene-3β,7α,17β-triol, dehydroepiandrosterone,4-dihydrotestosterone, 5α-dihydrotestosterone, dromostanolone,dromostanolone propionate, ethylestrenol, nandrolone phenpropionate,nandrolone decanoate, nandrolone furylpropionate, nandrolonecyclohexanepropionate, nandrolone benzoate, nandrolonecyclohexanecarboxylate, oxandrolone, stanozolol, testosterone, methyltestosterone, testolactone, oxymetholone, fluoxymesterone,acetoxypregnenolone, allylestrenol, anagestone acetate, chlormadinoneacetate, cyproterone, cyproterone acetate, desogestrel,dihydrogesterone, dimethisterone, ethisterone (17α-ethynyltestosterone),ethynodiol diacetate, fluorogestone acetate, gestadene,hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesteronecaproate, 3-ketodesogestrel, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, levonorgestrel, lynestrenol,medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate,melengestrol acetate, norethindrone, norethindrone acetate,norethisterone, norethisterone acetate, norethynodrel, norgestimate,norgestrel, norgestrienone, normethisterone, and progesterone,progesterone, cyproterone acetate, norethindrone, norethindrone acetate,levonorgestrel, an ester of any of the foregoing compounds (e.g.,acetate, enanthate, propionate, isopropionate, cyclopropionate,isobutyrate, butyrate, valerate, caproate, isocaproate, hexanoate,heptanoate, octanoate, nonanoate, decanoate, undecanoate, phenylacetateor benzoate esters, e.g., hydroxyl esters), a naturally occurringglucorcorticoid, a species disclosed herein or a derivative of any ofthese that can convert to these molecules by hydrolysis or metabolism,e.g., a metabolizable or hydrolyzable ester or ether such as a cyclicketal, an acetate, a diacetete, a proprionate, a diproprionate, or anO-alkyl, an acyl, e.g., —C(O)—C1-C6 alkyl or another moiety that isbonded at, e.g., a variable group such as for R¹-R⁶.

Dosages of F1C and dosing protocols or methods. In treating any of theconditions or symptoms disclosed herein, one can continuously orintermittently administer the F1C(s) to a subject having or susceptibleto developing the condition or symptom. In treating a condition such asan infection, a hyperproliferation condition, an inflammation conditionor another condition disclosed herein with a F1C using an intermittentdosing can avoid or ameliorate some of the undesired aspects normallyassociated with discontinuous dosing. Such undesired aspects includedevelopment of resistance of a pathogen such as a pathogen disclosedherein, e.g., a virus or bacterium such as HIV or Staphylococcus aureusor a parasite such as a Plasmodium parasite, to the therapeutic agent,failure of the patient or subject to adhere to a daily dosing regimen orreduction of the dosages of other therapeutic agents and/or theirassociated unwanted side effects or toxicities, e.g., reduction or atoxic effect of a chemotherapy or radiation exposure. In any of thecontinuous or intermittent dosing protocols described herein, otherappropriate treatments can be applied as the subject's clinicalsituation dictates. Suitable other appropriate treatments or therapeuticagents are described elsewhere herein and in the cited references.

In any of the continuous or in any step(s) in the intermittent dosingprotocols described herein, or in treating any of the diseases,conditions or symptoms described herein, the F1C(s) can be administeredby one or more suitable routes, e.g., oral, buccal, sublingual,intramuscular (i.m.), subcutaneous (s.c.), intravenous (i.v.),intradermal, another parenteral route or by an aerosol. The effectivedaily dose in such methods will typically comprise about 0.05 mg/kg/dayto about 200 mg/kg/day, or about 0.1 to about 100 mg/kg/day, includingabout 0.2 mg/kg/day, 0.5 mg/kg/day, about 1 mg/kg/day, about 2mg/kg/day, about 4 mg/kg/day, about 6 mg/kg/day, about 10 mg/kg/day,about 20 mg/kg/day, about 40 mg/kg/day or about 100 mg/kg/day. Higherdosages, e.g., about 250 mg/kg/day, about 300 mg/kg/day or about 350mg/kg/day can also be utilized, e.g., in veterinary applications. Onecan administer the F1C(s) orally using about 4 to about 60 mg/kg/day,usually about 6-30 mg/kg/day. In some embodiments, the intermittentdosing methods exclude dosing protocols that are commonly used todeliver contraceptive steroids to, e.g., human females, such as dailydosing for 21 days, followed by no dosing for 7 days. For humans, dosingis generally about 0.005 mg/kg/day to about 30 mg/kg/day, typicallyabout 0.5-5 mg/kg/day. Low dosages for humans such as about 0.005mg/kg/day to about 0.2 mg/kg/day or about 0.25-10 mg/day, can be usedwith, e.g., local, topical, transmucosal or intravenous administrationand higher dosages such as about 0.1 mg/kg/day to about 20 mg/kg/day orabout 5-200 mg/day, can be used, e.g., for oral, subcutaneous or othersystemic or local administration route. For non-human subjects, e.g.,mammals such as rodents or primates, the effective daily dosage maycomprise about 0.05 mg/kg/day to about 350 mg/kg/day. F1C formulationdosages or daily doses or unit doses or subdoses for subjects such ashumans and mammals include, e.g., about 1, 5, 10, 15, 20, 25, 50, 75,100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 400 or 450 mg ofthe F1C.

An effective dosage or an effective amount of a F1C(s) is one that issufficient to result in, e.g., a detectable change in a symptom or animmune parameter such as one described herein. An effective dosage (ordaily dosage) may be administered to a subject over a period of time,e.g., at least about 1-14 days before a symptom change or an immuneparameter detectably changes. Effective amounts of a F1C can bedelivered using the dosages and dosing protocols described herein.

In some embodiments, F1C are used to treat, ameliorate, prevent or slowthe progression of a condition or disease described herein by continuousdaily dosing of the F1C for 1 day to 1, 2, 3 years or more. In relatedembodiments, F1C are used to treat, ameliorate, prevent or slow theprogression of a condition or disease described herein by continuousdosing the F1C every other day or dosing every third, fourth, fifth,sixth, seventh or 14^(th) day over a time period of 3 days to 1, 2, 3years or more, e.g., dosing for about 2, 3, 4, 5, 6 or 7 days or about1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 or more weeks. Daily doses in anyof these dosing regimens or protocols may be subdivided into 2 or 3subdoses.

Intermittent dosing protocols include administration of a F1C, e.g.,orally, topically or parenterally as follows: (1) daily dosing or dosingevery other day or dosing every third day or dosing every fourth day ordosing every fifth day or dosing every seventh day for about 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 28 days toabout 190 days or more, e.g., 1 or 2 years, (2) no dosing of the F1C for1 to about 190 consecutive days (e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 days to about 20 days), (3) daily dosing for about 3 to about190 days (e.g., about 3 to about 20 days), and (4) optionally repeatingstep (2) or a variation of step (2) and (5) optionally repeating thesteps (1), (2), (3) and (4) 1, 2, 3, 4, 5, 6, 10, 15, 20, 30 or moretimes. In some embodiments, the dosing of steps (1) and (3) are thesame, while in others, step (1) dosing is for a longer time than step(3). Less frequently, step (1) dosing will be for a shorter time. Insome embodiments, steps (1)-(4) or (1)-(5) of the dosing protocoldescribed above where step (4) is included, is repeated at least onetime, e.g., at least 2, 3, 4, 5 or 6 times. For conditions that tend toremain chronic, e.g., HIV infection or other chronic conditionsdescribed herein, any of these intermittent dosing protocols can bemaintained over a relatively long time period, e.g., for at least about4 months or 6 months to about 5 or more years.

In some embodiments, the number of days of dosing in steps (1) and (3)is the same in each round of treatment, i.e., each time period in step(1) and (3) is the same in the initial and subsequent rounds of themethod. In other embodiments they differ. Thus, in some embodiments,step (1) may comprise dosing of about 1 mg/day to about 1500 mg/day of aF1C for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more consecutive days. Then,step (2) may comprise not administering any F1C for at least about 2, 3,4, 5, 6, 7, 14, 21, 28, 42, 56, 84, 98, 112 or more consecutive days.Step (3) could comprise dosing of a F1C for 1, 2, 3, 4, 5, 6, 7, 8, 9,10 or more consecutive days. When step (4) is included it is typicallyabout 1 day to about 3 months, usually 3 days to about 6 weeks. On dayswhen the F1C is administered to the subject, it may be delivered in asingle dose or in two, three or more subdoses at, e.g., about 12 hour orabout 8 hour time intervals.

One aspect of invention intermittent dosing is monitoring the subject'sresponse to a particular dosing regimen or schedule, e.g., to anyintermittent administration method disclosed herein. For example, whiledosing a subject who has a viral infection (e.g., HCV, HIV, SIV, SHIV),one can measure the subject's or pathogen's response, e.g., ameliorationof one or more symptoms or a change in infectious particles or viral DNAor RNA in the serum or a change in an immune parameter of interest. Oncea response is observed dosing can be continued for one, two or threeadditional days, followed by discontinuing the dosing for at least oneday (at least 24 hours), usually for at least about 2, 3, 4, 5, 6, 7,14, 21, 28, 42, 56, 70, 84, 98, 112 or more days. Once the subject'sresponse shows signs of remission (e.g., a symptom begins to intensify,viral serum DNA or RNA begins to increase or an immune parameter, e.g.,as described herein, begins to deteriorate), dosing can be resumed foranother course. An aspect of the subject's response to F1C(s) is thatthe subject may show a measurable response within a short time, usuallyabout 5-10 days, which allows straightforward tracking of the subject'sresponse, e.g., by monitoring viral titer in peripheral white bloodcells (“PBMC”), by measuring viral nucleic acid levels in the blood orby measuring a white blood cell population(s) or expression of acytokine or interleukin by e.g., white blood cells or a subset(s)thereof. One may monitor one or more immune cell subsets, e.g., NK, LAK,dendritic cells or cells that mediate ADCC immune responses, during andafter intermittent dosing to monitor the subject's response and todetermine when further administration of the F1C is indicated. Thesecell subsets are monitored as described herein, e.g., by flow cytometry.

Dosages of the F1C, continuous or intermittent dose protocols, routes ofadministration and the use of combination therapies with other standardtherapeutic agents or treatments could be applied essentially asdescribed above for any of the diseases or conditions that are disclosedherein. Thus, the F1Cs may be administered prophylactically ortherapeutically in chronic or acute conditions. In acute conditions, theF1Cs may also be administered at the time of occurrence or relativelysoon after an acute event such as the onset of surgery, a migraine orthe occurrence of trauma, e.g., a central nervous system injury, acerebral stroke or myocardial infarction. For acute events, a F1C maythus be administered concurrently, e.g., within about 15 minutes orabout 30 minutes or about 45 minutes of the onset or occurrence of theacute event, or at a later time, e.g., at about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 26, 28, 30, 36, 42, 48,54, 60, 72, 84, 96, 108 or 120 hours after the onset or occurrence ofthe acute event or at any range of times defined by any two of theselater times. The F1Cs may thus be administered at about 4-120 hours,about 6-120 hours, about 8-48 hours, 8-24 hours, 8-12 hours, 10-12hours, 10-14 hours, 10-16 hours, about 10-24 hours, 12-14 hours or about12-16 hours after an acute event starts, occurs or is believed to havebegun, e.g., after a surgical procedure has been completed or after aradiation treatment has ended or after a cytotoxic chemotherapy or amyelosuppressive cancer chemotherapy has been administered to thesubject.

Alternatively, the F1Cs may be administered before, e.g., within about15 minutes, about 30 minutes or about 45 minutes before the onset oroccurrence of a planned or anticipated acute event, or at an earliertime, e.g., at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 18, 20, 22, 24, 26, 28, 30, 36, 42, 48, 54, 60, 72, 84, 96, 108 or120 hours before the onset or occurrence of the acute event. The F1Csmay thus be administered at about 6-120 hours, about 8-48 hours, about10-24 hours, about 10-16, or about 12-16 hours before the planned oranticipated acute event, e.g., before a planned surgery or a radiationtreatment starts or occurs.

Formulations and compositions for preparing formulations. Inventionembodiments include formulations described here and elsewhere in thisdisclosure. While it is possible for the F1C(s) to be administered to asubject or incubated with a subject's cells in vitro as the compoundalone, it is usual to use F1C in a formulation or at least in acomposition that contains 1, 2, 3, 4, 5, 6 or more excipients. Theformulations, which are useful for veterinary or human pharmaceuticaluse, comprise at least one F1C, together with 1, 2, 3, 4, 5, 6 or moreexcipients and optionally one or more additional therapeuticingredients.

The invention includes compositions comprising one or morepharmaceutically acceptable excipients or carriers. The compositions areused to prepare formulations suitable for human or animal use.Formulations may be designed or intended for oral, rectal, nasal,topical or transmucosal (including buccal, sublingual, ocular, vaginaland rectal) and parenteral (including subcutaneous, intramuscular,intravenous, intradermal, intrathecal, intraocular and epidural)administration. In general, aqueous and non-aqueous liquid or creamformulations are delivered by a parenteral, oral or topical route. Inother embodiments, the F1C(s) may be present as an aqueous or anon-aqueous liquid formulation or a solid formulation suitable foradministration by any route, e.g., oral, topical, buccal, sublingual,parenteral, aerosol, a depot such as a subcutaneous depot or anintraperitoneal or intramuscular depot or a rectal or vaginalsuppository. The preferred route may vary with, for example, thesubject's pathological condition or weight or the subject's response totherapy with a F1C or other therapy that is used or that is appropriateto the circumstances. The F1C formulations can also be administered bytwo or more routes, e.g., subcutaneous injection and buccal orsublingual, where these delivery methods are essentially simultaneous orthey may be essentially sequential with little or no temporal overlap inthe times at which the compound is administered to the subject.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods known in the art ofpharmacy. Techniques, excipients and dosage forms are found in, e.g.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1985, 17^(th) edition; Nema et al., PDA J. Pharm. Sci. Tech. 199751:166-171; Pharmaceutical Coating Technology, 1995, G. Cole, et al.,editors, Taylor & Francis, ISBN 0 136628915; Pharmaceutical DosageForms, 1992 2^(nd) revised edition, volumes 1 and 2, H. A. Lieberman, etal., editors, Marcel Dekker, ISBN 0824793870; PharmaceuticalPreformulation, 1998, pages 1-306, J. T. Carstensen, TechnomicPublishing Co. ISBN 1566766907; and Encyclopedia of PharmaceuticalTechnology, volumes 1, 2 and 3, 2^(nd) edition, 2002, J. Swarbrick andJ. O Boylan, editors, Marcel Dekker, Inc., New York, N.Y.

Methods to make invention formulations include the step of bringing intoassociation or contacting a F1C(s) with one or more excipient, such asone described herein or in the cited references. In general theformulations are prepared by uniformly and intimately bringing intoassociation the F1C(s) with liquid excipients or finely divided solidexcipients or both, and then, if appropriate, shaping the product.

Formulations suitable for oral administration are prepared as discreteunits such as capsules, soft gelatin capsules (softgels), cachets,tablets or caplets each containing a predetermined amount of the F1C(s).F1C formulations can also be present as a powder or granules or as asolution or a suspension, colloid or gel in an aqueous liquid or base orin a non-aqueous liquid or base; or as an oil-in-water liquid emulsionor a water-in-oil liquid emulsion. The F1C formulations may also be abolus, electuary or paste. Suspension formulations will typicallycontain about 0.5% w/w or about 1% w/w to about 5%, 10%, 15% or 20% w/wof the F1C, which can be for parenteral use or for other routes ofadministration, e.g., oral softgels.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the F1C(s) in a free-flowing form such as a powderor granules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered orgranulated F1C and one or more excipients, which are optionallymoistened, with an inert liquid diluent or excipient. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the F1C(s) therefrom. An exemplarytablet or caplet formulation suitable for buccal or sublingual deliveryof a F1C to a subject's tissues comprises about 25 or 50 mg of a F1Ccomprising per 25 mg of the F1C about 6.2 mg povidone, about 0.62 mgmagnesium stearate, about 45 mg mannitol and about 48 mg of compressiblesucrose.

For infections of the eye or other external tissues e.g., the mouth orskin, the formulations are typically applied as a topical ointment orcream containing the F1C(s) in an amount of, for example, about 0.075 toabout 20% w/w (including F1C(s) in a range between about 0.1% and 20% inincrements of 0.1% w/w such as about 0.6% w/w, about 0.7% w/w, about 1%w/w, about 1.5% w/w, about 2% w/w, about 2.5 w/w, about 3% w/w, about 5%w/w, about 7% w/w, about 10% w/w etc.), including about 0.2 to 15% w/wand about 0.5 to 10% w/w. When formulated in an ointment, the F1C(s) maybe employed with either a paraffinic or a water-miscible ointment base.Alternatively, they may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, butane 1,4-diol, mannitol, sorbitol, glycerol and apolyethylene glycol (including, e.g., PEG 300 and PEG 400) and mixturesthereof. The topical formulations may include a compound that enhancesabsorption or penetration of the F1C(s) through the skin or otheraffected areas. Examples of such dermal penetration enhancers includedimethyl sulphoxide and related analogs.

The oily phase of the emulsion formulations may be constituted fromknown excipients in a known manner. While the phase may comprise anemulsifier or emulgent, it typically comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil. Ahydrophilic emulsifier may be included together with a lipophilicemulsifier, which acts as a stabilizer. Some embodiments include both anoil and a fat. Together, the emulsifier(s) with or without stabilizer(s)make up the so-called emulsifying wax, and the wax together with the oiland fat make up the so-called emulsifying ointment base which forms theoily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationsinclude Tween60™, Span80™, cetostearyl alcohol, benzyl alcohol, myristylalcohol, glyceryl mono-stearate and sodium lauryl sulfate. Otherexcipients include emulsifying wax, propyl gallate, citric acid, lacticacid, polysorbate 80, sodium chloride, isopropyl palmitate, glycerin andwhite petrolatum.

Formulations suitable for topical administration to the eye include eyedrops, which are usually sterile, wherein the F1C(s) is dissolved orsuspended in a suitable excipient(s), including an aqueous solvent for aF1C(s) that comprise at least about 0.5, one, two or more charges at pHvalues near neutrality, e.g., about pH 6-8. The F1C(s) is typicallypresent in such formulations in a concentration of about 0.5-20% w/w,about 1-10% w/w or about 2-5% w/w.

Formulations suitable for topical administration to oral mucosa includelozenges or tablets comprising the F1C(s) in a flavored basis or amonosaccharide or disaccharide such as sucrose, lactose or glucose andacacia or tragacanth; pastilles comprising the F1C(s) in an inert basissuch as gelatin and glycerin, or sucrose and acacia; and mouthwashescomprising the F1C(s) in a suitable liquid excipient(s). In someembodiments, the lozenges or tablets optionally comprise the property ofrapid dissolution or disintegration, e.g., disintegration within about15 seconds to about 2 minutes, while in others, the lozenges or tabletscomprise the property of slower dissolution or disintegration, e.g.,disintegration within about 2 minutes to about 10 minutes or more.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the F1C(s) such excipients as are known in theart to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats, salts (e.g., NaCl, potassium or sodium carbonateor bicarbonate or potassium or sodium phosphates) and solutes whichrender the formulation isotonic with the blood of the intended subject;and aqueous and non-aqueous sterile suspensions which may includesuspending agents or thickening agents. In general, the F1C that ispresent in liquid compositions or formulations is completely dissolvedin aqueous or non-aqueous excipients. However, in some embodiments,e.g., transient compositions or some formulations, the F1C is partiallydissolved while the remaining portion is present as a solid, which canbe a suspension or a colloid.

Formulations suitable for parenteral delivery of F1Cs to subjects suchas humans or animals typically comprise 1, 2, 3, 4, 5, 6 or moreexcipients. Exemplary embodiments include (1) any two, three or four ofpropylene glycol, PEG200, PEG300, ethanol, benzyl alcohol and benzylbenzoate and (2) any two, three or four of propylene glycol, PEG100,PEG200, PEG300, PEG400, benzyl alcohol and benzyl benzoate. Typicallysuch formulations will contain both propylene glycol and one or morePEGs, e.g., PEG100, PEG200, PEG300 or PEG400, which enhance thesolublity of the F1C by a cosolvent effect.

Formulations, or compositions disclosed herein for use to makeformulations suitable for administration by the routes disclosed hereinoptionally comprise an average particle size in the range of about 0.01to about 500 microns, about 0.1 to about 100 microns or about 0.5 toabout 75 microns. Average particle sizes include a range between 0.01and 500 microns in 0.05 micron or in 0.1 micron or other increments,e.g., an average particle size of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5,0.7, 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6, 7, 8, 9, 10, 15,20, 25, 30, 35, 40, 50, 60, 75, 85, 100, 120, 150, etc. microns). TheF1C itself that is used to make a formulation can have one, two or moreof these average particle sizes. When F1Cs or compositions that comprisea F1C are used as intermediates to make a formulation, they may compriseone, two, three or more of these average particle sizes, or size ranges.In preparing any of the compositions or formulations that are disclosedherein and that comprise a F1C (and optionally one or more excipients),one may optionally mill, sieve or otherwise granulate the compound orcomposition to obtain a desired particle size, e.g., as described above.

Milling or micronization by any other method may occur before or afterthe F1C is contacted with one or more excipients. For example, one maymill a F1C to obtain an average particle size (or diameter) of about0.05-50 μM or about 0.5-10 μM (e.g., about 0.02, 0.04, 0.05, 0.07, 0.1,0.5, 1, 1.5, 2, 2.5, 5, 10, 15, 20, 30, 40, 50, 60, 80, 100 or 120 μMaverage particle size or diameter) before contacting the milled F1C witha liquid or solid excipient. In some cases the F1C is milled or sievedto obtain an average particle size of about 5 μm or about 10 μm beforeit is contacted with a solid or liquid excipient(s) to obtain a solutionor suspension or a powder suitable for making a tablet, capsule or otherdosage form as described herein or in the cited references. Micronizedcompound may be prepared using any suitable process for obtaining smallparticles, e.g., controlled precipitation from a solution, micronizingor milling, a number of which are known in the art. The micronizedparticles may include a percentage of particles that are less than orequal to about 0.1-20 μm in diameter. Ranges of average particle sizesinclude F1Cs of about 0.04-0.6 μm, about 0.04-1.0 μm, about 0.05-0.6 μm,about 0.05-1.0 μm, about 0.1-0.4 μm, about 0.5-1 μm, about 1-20 μm orabout 2-50 μm.

As used herein, reference to an average particle size or an averageparticle diameter means that the material, e.g., a F1C(s), anexcipient(s) or a composition that comprises both, is ground, milled,sieved or otherwise treated so as to comprise the specified averagesize. It is to be understood that some particles may be larger orsmaller, but the composition or the F1C(s) will comprise a significantproportion of the material with the specified size or within anacceptable range of the specified size, e.g., at least about 70% orabout 80% of the particles within about 30% to about 50% of the averagesize or diameter. Micronization methods include milling by ball mills,pin mills, jet mills (e.g., fluid energy jet mills) and grinding,sieving and precipitation of a compound(s) from a solution, see, e.g.,U.S. Pat. Nos. 4,919,341, 5,202,129, 5,271,944, 5,424,077 and 5,455,049.Average particle size is determined by known methods, e.g., transmissionelectron microscopy, scanning electron microscopy, light microscopy,X-ray diffractometry, light scattering methods or Coulter counteranalysis.

Thus, the F1Cs may comprise a powder that consists of one, two or moreof these average particle sizes and the powder may be contacted with asolid excipient(s), suitably mixed and optionally compressed or formedinto a desired shape. Alternatively, such a F1C(s) is contacted with aliquid excipient(s) to prepare a liquid formulation or a liquidcomposition that is incorporated into a solid formulation. Suitablemicronized formulations thus include aqueous or oily solutions orsuspensions of the F1C(s).

Formulations suitable for aerosol administration typically will comprisea fine powder, e.g., having an average particle size of about 0.1 toabout 20 microns or any one, two or more of the average particle sizeswithin this range that are described above. The powder is typicallydelivered by rapid inhalation through the nasal passage or by inhalationthrough the mouth so as to reach the bronchioles or alveolar sacs of thelungs.

Formulations suitable for aerosol, dry powder or tablet administrationmay be prepared according to conventional methods and may be deliveredwith other therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis of viral or other infections as describedherein. Such formulations may be administered, e.g., orally,parenterally (e.g., intravenous, intramuscular, subcutaneous,intradermal, intrathecal), topically, sublingually or by a buccal orsublingual route.

Micronized F1C is useful, e.g., to facilitate mixing, dissolution oruniform suspension of the F1C in one or more liquid or solid excipients,e.g., a PEG such as PEG 300 or PEG 400, propylene glycol, benzylbenzoate, a complexing agent, such as a cyclodextrin (e.g., an α-, β- orγ-cyclodextrin such as hydroxypropyl-β-cyclodextrin). Micronized F1C isalso useful to facilitate uniformly distributing drug substance when themicronized compound is contacted with one or more solid excipients(e.g., a filler, a binder, a disintegrant, complexing agent (e.g., acyclodextrin such as hydroxypropyl-β-cyclodextrin), a preservative, abuffer or a lubricant).

In related embodiments, suitable compositions or formulations comprise aF1C that is present in two or more physical forms. For example, a liquidcomposition or formulation may comprise a F1C that is present insolution and as undissolved particles, which may be milled as describedherein. Alternatively, a solid composition or formulation may comprise aF1C that is present as an amorphous form and as a crystal or in anencapsulated granule. Such encapsulated granules may comprise a slowrelease type formulation and the F1C that is present may be in one ormore physical forms, e.g., liquids or solids as described herein, butusually as a solid in tablets or other solid formulations.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid excipient, for example water for injection, immediatelyprior to use. In general, solid, liquid or other formulations orcompositions that comprise a F1C, e.g., unit dosages for solid or liquidformulations, are stored in a sealed container, which may optionally beopaque or nearly opaque (e.g., amber or blue glass or brown plastic) toreduce the amount of light that reaches the formulation or composition.Such containers are also optionally sealed, e.g., hermetically sealed,to prevent or limit exchange of air, water or other gases between thecontainer's contents and air. Extemporaneous injection solutions andsuspensions are prepared from sterile powders, granules and tablets asdescribed above. Unit dosage formulations are those containing a dailydose or unit daily sub-dose, as recited herein, or an appropriatefraction thereof, of the F1C(s).

Invention formulations include controlled release or slow releaseformulations containing a F1C(s) in which the release of the F1C(s) iscontrolled or regulated to allow less frequency dosing or to improve thepharmacokinetic or toxicity profile of a given F1C(s). Polymers andother materials that are suitable to prepare controlled releaseformulations that comprise a F1C have been described, e.g., U.S. Pat.Nos. 4,652,443, 4,800,085, 4,808,416, 5,013,727, 5,188,840.

Formulations may thus contain microcapsules, granules or other shapedforms and may comprise a F1C and a slow release polymer or polymermatrix that comprises or consists of one or more of ethylenedimethacrylate, diethylene glycol dimethacrylate, diethylene glycoldiacrylate, triethylene glycol dimethacrylate, triethylene glycoldiacrylate, tetrathylene glycol dimethacrylate, tetraethylene glycoldiacrylate, polyethylene glycol dimethacrylate, polyethylene glycoldiacrylate, diethylaminoethyl dimethacrylate, glycidyl methacrylate,epoxy acrylate, glycidyl acrylate, hydroxyethyl methacrylate,hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxypropylacrylate, hydroxybutyl methacrylate, hydroxybutyl acrylate, hydroxyhexylmethacrylate, hydroxyhexyl acrylate, butanediol dimethacrylate,butanediol diacrylate, propanediol dimethacrylate, propanedioldiacrylate, pentanediol dimethacrylate, pentanediol diacrylate,hexanediol dimethacrylate, hexanediol diacrylate, neopentyl glycoldimethacrylate, neopentyl glycol diacrylate, trimethylopropanetriacrylate, trimethylolpropane trimethacrylate, trimethyloethanetriacrylate, trimethylolethane trimethacrylate, polypropyleneglycoldiacrylate, and polypropylene glycol dimethacrylate.

Invention embodiments include the product made by a process ofcombining, mixing or otherwise contacting a F1C and one, two or moreexcipients. Such products are produced by routine methods of contactingthe ingredients. Such products optionally contain a diluent, adisintegrant, a lubricant, a binder, or other excipients describedherein or in references cited herein.

When a F1C and an excipient(s) is contacted or mixed, the finalcomposition may comprise a homogenous mixture or it may comprise amixture that is not homogenous for one or more of the compounds that arepresent in the composition. Compositions and formulations that areeither homogenous or non-homogenous are included in the scope of theinvention. Non-homogenous compositions can be used, e.g., to makecontrolled release formulations.

Other embodiments include the product obtained by storing inventioncompositions or formulations, e.g., unit dosage forms or compositionsused to make formulations, at about 4-40° C. for at least about 30 days,e.g., storage at ambient temperature for about 1-24 months. Inventionformulations will typically be stored in hermetically or inductionsealed containers for these time periods. Compositions and formulationsthat comprise a F1C will typically be held in closed or sealedcontainers, particularly when the composition is a formulation forpharmaceutical or veterinary use.

Typical containers for storage of compositions and formulations thatcomprise a F1C will limit the amount of water that reaches the materialscontained therein. Typically, formulations are packaged in hermeticallyor induction sealed containers. The containers are usually inductionsealed. Water permeation characteristics of containers have beendescribed, e.g., Containers—Permeation, chapter, USP 23 <671>, UnitedStates Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway,Rockville, Md. 20852, pp.: 1787 et seq. (1995).

Immune modulation. The F1Cs, or the biologically active substancesproduced from these compounds by hydrolysis or metabolism in vivo, havea number of clinical and non-clinical applications. The compounds aregenerally useful to correct immune dysregulation, e.g., imbalancedimmune responses to disease conditions, pathogens or the like,suppression of an innate or acquired immune response(s) and inflammationconditions in vertebrate or mammalian subjects, e.g., as disclosedherein. Thus, while the compounds will generally enhance a deficientimmune response in a given clinical condition, they will generallyreduce the same immune response when it is too active in a differentclinical condition. For example, they can enhance insufficient orsuboptimal Th1 immune responses, reduce excess or undesirable Th2 immuneresponses, reduce excess or undesirable Th1 immune responses or enhanceinsufficient or suboptimal Th2 immune responses or they can reduceexcess or undesirable inflammation or one or more of its symptoms. Thecompounds will generally also modulate dysregulated Tc1 and Tc2 immuneresponses (associated with CD8⁺ T cells) in a similar manner, e.g.,excessive Tc1 or Tc2 responses will be detectably decreased anddeficient or suboptimal Tc1 or Tc2 responses will generally bedetectably enhanced.

Invention embodiments include a method to modulate a subject's innateimmunity, Th1 immune responses, Tc1 immune responses, Th2 immuneresponses or Tc2 immune responses comprising administering an effectiveamount of a F1C to a subject or delivering the F1C to the subject'stissues. Other methods include modulating an immune or cellular responsein a subject in need thereof comprising administering to the subject, ordelivering to the subject's tissues, an effective amount of a compoundof formula 1. Immune and cellular response modulation includes enhancingTh1 immune responses, reducing Th2 immune responses, reducing Th1 immuneresponses, enhancing Th2 immune responses, reducing unwanted orpathological inflammation, enhancing hematopoiesis or modulating thesynthesis, level or a biological activity of a biomolecule such as (1) atranscription factor such as a nuclear hormone receptor or an associatedreceptor factor, (2) a purine such as adenosine, (3) a nucleotidecofactor such as NADPH, (4) a cytokine or interleukin or a receptor fora cytokine or interleukin, or (5) another biomolecule as disclosedherein. Such enhancements, reductions, levels or activities are usuallyin an easily detectable range, e.g., a change compared to a suitablecontrol of at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 95% or a range that is between about any two of these values.Typically the subject is in need of such treatment, e.g., by having aclinical condition disclosed herein or being subject to developing sucha condition, e.g., having been exposed or potentially exposed to apathogen or having a predisposing condition such as precancer.

In modulating one or more activities of Th1, Th2, Tc1 or Tc2 cells ortheir function(s), the F1Cs will typically detectably modulate one, two,three or more factors, e.g., immune cell subsets or populations,cytokines, interleukins, surface antigens such as a CD molecule(s)and/or their receptors that affect the development, migration, numbersor biological function(s) of such cells. When a Th1 or Tc1 cell orpopulation is affected, the F1Cs will typically increase or decrease thesynthesis or level of one, two or more of an associated effector factor,e.g., IFNγ, IL-2, IL-12, IL-18, T-bet, PPARα and PPARγ or a cell surfacemolecule, e.g., as disclosed herein or in the cited references, that isassociated with or needed for normal, optimal or enhanced Th1 or Tc1cells or cell function. Such molecules are generally associated withdevelopment or enhancement of Th1 or Tc1 cells or their biologicalfunction(s). When a Th2 or Tc2 cell or population is affected, the F1Cswill typically increase or decrease the synthesis or level of one, twoor more of an associated effector factor, e.g., IL-4, IL-5, IL-6, IL-8,IL-10, IL-13, GATA-3, COX-2 or a cell surface molecule, e.g., asdisclosed herein or in the cited references, that is associated with orneeded for normal, optimal or enhanced Th2 or Tc2 cells or cellfunction(s). Such molecules are generally associated with development orenhancement of Th2 or Tc2 cells or their biological function(s).

Similarly, when a subject has or is subject to developing an unwanted orexcessive inflammation, the F1Cs will generally detectably modulate oneor more relevant effector factors for inflammation, e.g., a detectabledecrease of one, two, three or more of IL-1α, IL-1β, TNFα, TNF-β,MIP-1α, MIP-2, TGF-β1, IP-10, LT-β, γIFN, IL-6, IL-8, IL-10 and COX-2,lipoxygenase, or an increase of one or more suppressor factors orantagonists of inflammation. Such modulation can comprise increases ordecreases of at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 200%, 300%, 500%, 1000%,5000% or within a range between any two of these values, e.g., betweenabout 5-95%, about 10-90%, about 5-60% or about 40-95%. In general, suchchanges leads to a detectable amelioration of an inflammation-associateddisease, condition, symptom or to the detectable slowing of theprogression thereof or to a detectably reduced incidence or severity ofor susceptibility to developing an unwanted inflammatory response.

In conditions where an unwanted or excessive Th1, Tc1, Th2 or Tc2response is associated with or causes a disease(s), disease(s)progression, disease(s) state maintenance, condition(s) or symptom(s),the F1Cs will generally decrease the level or one or more biologicalactivity of one, two or more of their respective associated effectormolecules. In conditions where a deficient or suboptimal Th1, Tc1, Th2or Tc2 response is associated with or causes a disease(s), disease(s)progression, disease(s) state maintenance, condition(s) or symptom(s),the F1Cs will generally increase the level or one or more biologicalactivity of one, two, three or more of their respective associatedeffector molecules. Such changes in the level or biologicalactivity(ies) the associated effector molecules is generally detectableusing standard methods and is typically an increase (when a response isinsufficient) or a decrease (when a response is in excess) of at leastabout 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%,85%, 90%, 95%, 98% or within a range between any two of these values,e.g., between about 5-95%, about 10-90%, about 5-60% or about 40-95%. Ingeneral, such changes leads to a detectable amelioration of a disease,condition, symptom or to the detectable slowing of the progressionthereof or to a detectably reduced incidence or severity of orsusceptibility to developing a disease(s) or the occurrence of asymptom(s) for a at least a portion of subjects that are treated with aF1C, e.g., at least about 5%, 10%, 20%, 40%, 60% or 80% of treatedsubjects. The F1Cs may facilitate the clinical cure of a disease(s),prolong remission of a disease(s) or eliminate or ameliorate aclinically detectable symptom(s).

The F1C will generally also affect the function of other immune cellsubsets in a similar manner. Thus, when an insufficient macrophage,dendritic cell or neutrophil response is associated with theestablishment, maintenance or progression of a disease, symptom or acondition, the F1Cs will generally enhance of the level or a biologicalactivity(ies) of one or more effector molecule associated with or neededfor an optimal or more normal response or immune function that ismediated by the macrophages, dendritic cells or neutrophils. Similarly,when the subject suffers from a excessive or pathological activityassociated with macrophages, dendritic cells or neutrophils, which isassociated with the establishment, maintenance or progression of adisease, symptom or a condition, the F1Cs will generally detectablyreduce the level or a biological activity(ies) of one or more effectormolecule associated with or needed for an optimal or more normalresponse or immune function that is mediated by the macrophages,dendritic cells or neutrophils. Such effector molecules are as describedherein or in the cited references.

As used herein, reference to Th1 or Th2 immune responses means suchresponses as observed in mammals generally and not as observed in themurine system, from which the Th1 and Th2 terminology originated. Thus,in humans, Th1 cells are CD4⁺ T lymphocytes and they usuallypreferentially display chemokine receptors CXCR3 and CCR5, while Th2cells are CD4⁺ T lymphocytes and usually preferentially express theCCR4, CCR8 and/or CXCR4 chemokine receptor molecule(s) and generally asmaller amount of CCR3, see, e.g., U. Syrbe et al., Springer Semin.Immunopathol. 1999 21:263-285, S. Sebastiani et al., J. Immunol. 2001166:996-1002. Tc1 and Tc2 immune responses are mediated by CD8⁺lymphocytes and means to identify these cells and their associatedlymphokines, cell specific antigens and biological activities have beendescribed, see, e.g., M. B. Faries et al., Blood 2001 98:2489-2497, W.L. Chan et al., J. Immunol. 2001 167:1238-1244, C. Prezzi et al., Eur.J. Immunol. 2001 31:894-906, H. Ochi et al., J. Neuroimmunol. 2001119:297-305, D. H. Fowler and R. E. Gress, Leukemia and Lymphoma 200038:221-234.

The F1Cs are useful in reestablishing normal immune function in variousimmune dysregulation or immune suppression conditions. For example, theyare useful to treat, slow progression of or to ameliorate one or moresymptoms associated with one or more of an autoimmune condition(s), ainflammation condition(s), an infection(s), a cancer(s), a precancer(s),a chemotherapy(ies), radiation therapy, a burn(s), a trauma(s), asurgery(ies), a pulmonary condition, a cardiovascular disease(s) and aneurological or neurodegenerative disease(s). Without being limited toany theory, the F1Cs are believed to act through several mechanisms,including by directly or indirectly modulating nuclear hormone receptoractivity or by affecting or modulating other biological targets such astranscription factors, steroid binding proteins or enzymes in at leastsome of the diseases, conditions or symptoms disclosed herein.

The F1Cs are useful to modulate delayed-type hypersensitivity (“DTH”)responses and anergic conditions in subjects having to subject todeveloping abnormal DHT responses or anergy. Means to measure suchresponses and conditions are known and can be used to characterize theeffects of the F1Cs on these responses and conditions. See, e.g., A. E.Brown, et al., J. Med. Assoc. Thailand 83:633-639 2000, R. A. Smith etal., J. Adolesc. Health 27:384-390 2000, N. M. Ampel, Med. Mycology37:245-250 1999. The compounds will generally detectably enhance orrestore DTH in immune suppression conditions. They will also generallydetectably reduce or eliminate anergy in subjects having significantlyreduced or no immune response to, e.g., specific antigens or pathogens.

Clinical indications that have an association with or have a symptom(s)that is consistent or associated with an excessive or unwanted Th2immune response include, e.g., fatigue, pain, fever or an increasedincidence of infection, schizophrenia, acute myelitis, tumorprogression, progressive systemic sclerosis, Omenn's syndrome, atopicdisease, atopy, allergen hypersensitivity, atopic asthma, atopicdermatitis, burns, trauma (e.g., bone fracture, hemorrhage, surgery),immune responses to xenotransplantation, chronic periodontitis, SLE(systemic lupus erythematosus), discoid lupus erythematosus,osteoporosis, myasthenia gravis, Graves disease, mite-associatedulcerative dermatitis, rheumatoid arthritis and osteoarthritis.Excessive Th2 immune responses are also associated with an unwantedsymptom or pathology, e.g., fatigue, pain, fever or an increasedincidence of infection, that is associated with aging, allergy andinflammation conditions such as allergic bronchopulmonary aspergillosisin cystic fibrosis patients, allergic respiratory disease, allergicrhinitis, atopic dermatitis, subepithelial fibrosis in airwayhyperresponsiveness, chronic sinusitis, perennial allergic rhinitis,fibrosing alveolitis (lung fibrosis). This common underlying immunecomponent is at least part of the pathology or symptoms of all of theseconditions. This allows a F1C to be effectively used to prevent or treatthe condition or to treat or ameliorate one or more symptoms that areassociated with these conditions. Thus, in some embodiments, an unwantedor excessive Th2 response is present and amelioration of one or moresymptoms associated with this condition is accomplished by administeringan effective amount of a F1C according to the methods described herein,e.g., F1C is administered using a formulation and a route ofadministration essentially as described herein on an intermittent or adaily basis.

Typically, unwanted Th2 immune responses are associated with, or causedby, increased expression of one or more cytokines or interleukins suchas one, two, three or more of cortisol, IL-4, IL-5, IL-6, IL-10 andIL-13. Administration of a F1C will generally reduce the expression ofone or more of the Th2-associated cytokines or interleukins. At the sametime, the compounds generally enhance the expression of one or morecytokines or interleukins associated with Th1 immune responses. Becauseof their capacity to modulate or to balance Th1 and Th2 immuneresponses, the compounds are useful for a variety of clinicalconditions, e.g., infection, immunosuppression or cancer, where anenhanced Th1 immune response is desired. Effects of the F1Cs intreating, preventing or slowing the progression of the clinicalconditions described herein can include one or more of (1) enhancing theTh1 character of a subject's immune response or immune status, (2)increasing the intensity of a Th1 or a Th2 immune response or both and(3) decreasing inflammation or a symptom thereof.

Exemplary conditions where an immune imbalance or an excessive Th1immune response is involved include autoimmune diseases such as multiplesclerosis, Crohn's disease (regional enteritis), ulcerative colitis,inflammatory bowel disease, rheumatoid arthritis, reactive arthritis,acute allograft rejection, sarcoidosis, type 1 diabetes mellitus,Helicobacter pylori associated peptic ulcer, graft versus host diseaseand Hashimotos' thyroiditis. Because these conditions are associatedwith a similar type immune dysfunction, a F1C can be effectively used toprevent or treat these conditions or to treat or ameliorate one or moresymptoms associated therewith. Thus, in some embodiments, an unwanted orexcessive Th1 response is present and amelioration of one or moresymptoms associated with this condition is accomplished by administeringan effective amount of a F1C according to the methods described herein,e.g., F1C is administered using a formulation and a route ofadministration essentially as described herein on an intermittent or adaily basis. In other embodiments, an deficient Th1 response isenhanced, which is optionally observed as a detectable increase in oneor more of IFNγ, IL-2, IL-12 or IL-18 in Th1 cells or in accessory cellssuch as a dendritic cell or macrophage. In all of the conditions wherean insufficient or excess Th1, Th2, Tc1 or Tc2 response is present,amelioration of one or more symptoms associated with the condition isaccomplished by administering an effective amount of a F1C according tothe methods described herein.

Aspects of the invention include the use or administration ofcompositions or formulations that comprise a carrier and an amount of atleast one F1C effective to detectably modulate an immune parameter. Forexample, to enhance the relative proportion of a desired immune cellsubset, e.g., CD4⁺ T cells, CD8⁺ T cells, NK cells, LAK cells,neutrophils, granulocytes, basophils, eosinophils or dendritic cells, orto modulate (detectably increase or decrease) one or more functions ofimmune cell subsets. The F1Cs can modulate the expression of CDmolecules or alter the proportion of cell subsets, e.g., CD4⁺ or CD8⁺ Tcells, or their relative numbers in a subject's blood or tissues. CD andrelated molecules participate in the function of various immune cellsubsets and can be useful as markers for immune function in vivo. Insome aspects, the F1Cs activate immune cells which generally alters(increases or decreases) expression of, or changes the numbers of cellsthat express one or more of, CD4, CD6, CD8, CD25, CD27, CD28, CD30,CD36, CD38, CD39, CD43, CD45RA, CD45RO, CD62L, CD69, CD71, CD90 orHLA-DR molecules. Often, the numbers of cells that express thesemolecules are increased, e.g., CD25, CD36, CD16 or CD69. Typically, suchincreases are observed as an increased proportion of circulating whiteblood cells that express one or more of these molecules or white bloodcells, e.g., T cells or dendritic cells, that express CXCR3, CCR5, CCR4,CCR8 and/or CXCR4. In some cases the number of such molecules per cellis detectably altered.

Expression of one or more adhesion molecules CD2, CD5, CD8, CD11a,CD11b, CD11c, CD18, CD29, CD31, CD36, CD44, CD49a, CD49b, CD49c, CD49d,CD49e, CD49f, CD50, CD54, CD58, CD103 or CD104 are also detectablymodulated after administration of the F1Cs to a subject. Often, thenumbers of cells that express these molecules are increased, e.g., CD5or CD56. The adhesion molecules function in various aspects of immuneresponses, such as binding to class I MHC molecules, transducing signalsbetween cells or binding to molecules in the extracellular matrixassociated with endothelial or other cell types. Administration of theF1Cs to a subject also affects the numbers of certain immune cellsubsets, e.g., NK cells (e.g., CD8⁻, CD56⁺ or CD8⁺, CD56⁺) or lymphokineactivated killer cells (LAK). Increased circulating NK or LAK cells aretypically observed, which is reflected in increased numbers of cellsthat express one or more of CD16, CD38, CD56, CD57 or CD94. Also,increased numbers of circulating dendritic cell precursors are observed,as shown by increases in cells that express one or more of CD11c, CD80,CD83, CD106 or CD123. Although one can observe an increased proportionof circulating white blood cells that express one or more of thesemolecules, in some instances the number of such molecules per cell isdetectably altered. Both the cell numbers and the density of CD moleculeper cell can also be detectably modulated. Modulation of immune cellsubsets typically occurs on intermittent dosing of a F1C, but will arisefrom any suitable dosing regimen, e.g., as described herein.

Expression of one or more homing or other receptors or receptor subunitssuch as CD62L, CLA-1, LFA1, CD44, ICAM, VCAM or ECAM may also bedetectably affected after administration of the F1Cs to a subject. Thenumbers of cells that express these molecules, or the relative amountsper cell of, e.g., CD44 or CD62L, may be increased where a desiredimmune response is desired, e.g., migration of T cells to mucosaltissues or exposure of naïve T cells to antigen in lymph nodes.Alternatively, numbers of cells that express these molecules, or therelative amounts per cell of, e.g., CLA-1, may be decreased whereinhibition of an undesired immune response, such as an inflammatoryresponse is desired. The subject's response to such enhanced expressionincludes migration of cells such as movement of naïve T cells toperipheral lymph nodes in response to modulation of CD62L or otherhoming receptor expression. Thus, the F1Cs can also facilitate migrationof various immune cell types, e.g., dendritic cells, NK cells, LAKcells, macrophages or lymphocytes, from one location to another within asubject. For example, the compounds can enhance dendritic cell orlymphocyte migration from areas such as the skin tissues to the gutassociated lymphoid tissue (“GALT”), lymph nodes or spleen. Suchmigration may facilitate the function of those cell types by increasingtheir transit to tissues where their effector functions, e.g., antigenpresentation by dendritic cells, normally occur. The migration period isoften relatively transient (e.g., observable over about 1-7 days) oroccasionally longer (e.g., occurring for about 8-40 days), depending onthe dosing regimen and other factors. This migration can be observed bystandard methods, e.g., by cell staining, by PCR analyses or bydetermining the presence of a given cell type in circulation ordetermining a decrease in the number circulating cells. A decrease wouldgenerally reflect sequestration of an immune cell population(s) in atissue(s) where the immune cell normally exercises its effectorfunctions.

Thus, in some embodiments, the migration of one or more immune cellsubsets such as CD11C⁺ cells from tissue such as skin or lung throughthe blood to immune tissue such as lymph nodes or GALT is seen as atransient increase in the level of circulating CD11C⁺ cells in responseto exposure of the subject's tissues to a suitable amount of a F1C.Thus, the level of CD11C⁺ cells in the blood will generally detectablyincrease, e.g., a statistically significant increase, plateau and thendecrease as migration of the cells to immune tissue subsides. In theseembodiments, the proportion of the cells of the affected immune cellsubset is typically relatively low in most physiological immune states,e.g., normal or abnormal immune conditions, compared to the total whiteblood cell population in circulation. In other embodiments, themigration of one or more immune cell subsets such as CD123⁺ cells fromthe circulation to immune tissue such as lymph nodes or GALT results ina decrease. In these embodiments, the decrease in the numbers ofcirculating immune cells reflects the migration of the immune cells fromthe blood to immune tissue such as lymph nodes or GALT. Such a decreasemay be transient and followed by recovery of the affected immune cellsubset(s) over about 2 to 24 weeks. In conducting these embodiments,administration of the F1C to the subject is accomplished using theformulations or the methods as described herein.

Thus, an aspect of the invention is a method to enhance the migration ofone or more immune cell types in a subject from one location (e.g., bonemarrow, circulating blood or a tissue such as the skin, liver, centralnervous system or lung) to another (e.g., to the blood or to a lymphoidtissue such as a lymph node, spleen or a mucosal tissue such as GALT) byadministration to a subject as described herein of an effective amountof a F1C essentially as described by any of the methods disclosedherein. A related aspect is the monitoring, e.g., by suitable bloodcounts or tissue biopsy, of the subject's response to determine thetiming and extent of such immune cell migration.

Other CD molecules that are modulated by the presence of the F1Cs in asubject include cytokine receptor molecules such as one or more ofCD115, CDW116, CD117, CD118, CDW119, CD120a, CD120b, CD121a, CD121b,CD122, CD123, CD124, CD125 CD126, CDW127, CDW128 or CDW130. Often, thenumbers of receptor molecules per cell will be modulated. For example,receptors for cytokines that mediate or facilitate Th1 immune responsesor innate immune responses (e.g., one or more of IL-1α, IL-β, IL-2,IL-4, IL-12, γIFN or α-interferon) will typically increase in or oncells that mediate Th1 or innate immune responses. Modulation of thesemolecules may be by direct interactions with a receptor(s) in the cellthat expresses the cytokine receptor or indirectly by modulation ofcytokine synthesis in the affected cells or in other cells, typicallyimmune cells that may interact with the cells whose receptor synthesisis being modulated. Thus, autocrine or paracrine mechanisms may underliesome of the effects associated with administration of a F1C(s) such asaltered cytokine profiles in immune cells or altered immune cellpopulations. Endocrine cytokine mechanisms may also contribute todesired immune responses.

Treatment of a subject with a F1C can result in a change of at leastabout 20-80% or about 25-50% above or below (e.g., at least 30% or atleast 40% above or below) the control or basal level of affected immunecell subsets. For example, increases of more than about 30% in the totalnumbers of activated CD8⁺ T cells, e.g., CD8⁺, CD69⁺, CD25⁺ T cells,CD8⁺, CD69⁺, CD25⁻ T cells or CD8⁺, CD69⁻, CD25⁺ T cells, can occur by 7days after a single dose of a F1C to a subject. Such increases may begreater than 50%, 60% or 100% in the total numbers of activated CD8⁺ Tcells or subsets of activated CD8⁺ T cells in individual subjects.Typically such increases are about in the total numbers of activatedCD8⁺ T cells or subsets of activated CD8⁺ T cells averages about 30-40%,with individual subjects experiencing increases over 100% in the numbersof activated CD8⁺ T cells per unit blood volume compared to the basallevel.

Administration of the F1Cs can affect other immune cell subsets. Forexample, the concentration of circulating CD4⁺, CD69⁺, CD25⁻ (Th1 helpercells) and CD8⁺, CD16⁺, CD38⁺ LAK cells or CD8⁻, CD16⁺, CD38⁺ LAK cellstypically increases during or after the course of dosing a subject witha F1C. Also, CD8⁻, CD16⁺, CD38⁺ and CD8⁺, CD16⁺, CD38⁺ (ADCC effectorcells) and low side scatter Lin⁻, DR⁺, CD123⁺ (dendritic precursors) orlow side scatter Lin⁻, DR⁺, CD11c⁺ (dendritic cells or precursors) mayshow modest to significant increases.

In subjects that are immunosuppressed, e.g., from certain infections(e.g., viral (HIV, HCV), bacterial infection or parasite infection) orfrom chemotherapy (e.g., an antiviral therapy, a cancer chemotherapy ora radiation therapy), administration of the F1Cs to the subject resultsin a favorable shift in the balance of Th1 or Th2 responses the subjectcan mount in the face of immunosuppression. When Th1 responses aresuboptimal or insufficient, treatment with a F1C results in enhancementof Th1 responses or a reduction in Th2 responses. Conversely, when Th2responses are suboptimal or insufficient, treatment with a F1C resultsin enhancement of Th2 responses, which may occur with a concomitantmodulation (increase or decrease) in Th1 responses. The F1Cs can thus beused to shift the nature of a subject's immune response to result in amore balanced immune response from immunosuppression. Alternatively, thecompounds can selectively suppress inappropriate or unwanted immuneresponses. Enhanced Th1 responses appears to be at least partly due toone or more of (i) a reduction in biological restraints, e.g., highlevels of IL-4 or IL-10, on Th1 functions by preexisting primed Th1effector cells, (ii) enhanced differentiation of Th0 cells to Th1 cellsor enhanced responses mediated by Th1 cells, (iii) enhanced function ofaccessory cell function, e.g., antigen presentation by dendritic cells,dendritic precursor or progenitor cells or by macrophages or theirprecursors or progenitors, (iv) enhanced proliferation anddifferentiation of Th1 precursor or progenitor cells, (v) enhanced IL-12expression in dendritic cells or their precursors, which results inenhanced differentiation of Th1 cells from Th0 precursors, (vi) enhancedexpression or activity of factors associated with Th1 functions, e.g.,IL-2, gamma interferon (γIFN or IFNγ), IL-18 or lymphotoxin.

An aspect of the invention methods is an alteration in the expression ofIL-4 or IL-10 that occurs after administration of a F1C to a subject. Aconsistent observation is that extracellular IL-4 or IL-10 levelsrapidly decrease to levels that are undetectable by ELISA. IntracellularIL-10 levels are reduced to levels that are near or below the limits ofdetection by flow cytometry. The administration of a F1C to a subjectthus provides a means to inhibit either or both of these interleukins.Such inhibition may be associated with enhancement of Th1 immuneresponses relative to Th2 or Th0 responses, e.g., in subjects where Th1responses are suppressed (e.g., from viral, bacterial or parasiteinfection (HIV, HCV, etc) or chemotherapy) or are otherwise suboptimal.In many subjects, levels of either IL-4 or IL-10, usually IL-10, beforedosing with a F1C is low or undetectable. In these subjects, dosing withthe F1C results in a rapid drop in the interleukin that is detectable,usually IL-4.

Clinical conditions are described in more detail below where the F1Csare useful for treating, preventing, slowing the progression of, orameliorating one or more symptoms associated with the describedconditions. In any these conditions, any F1C disclosed herein can beused according to one or more of the dosing methods that are disclosedherein. For these conditions, dosages for the F1Cs, formulations androutes of administration are as described herein. Additional informationregarding these and other clinical conditions or symptoms that can betreated, prevented or ameliorated with the F1Cs are found at e.g., TheMerck Manual, 17^(th) edition, M. H. Beers and R. Berkow editors, 1999,Merck Research Laboratories, Whitehouse Station, N.J., ISBN0911910-10-7, or in other references cited herein.

Responses to treatment of a subject having a condition disclosed hereinwith a F1C is optionally monitored by observing changes in one or moreimmune or other appropriate clinical parameters, e.g., as describedherein or in D. S. Jacobs et al., editors, Laboratory Test Handbook,4^(th) edition, pages 11-686, Lexi-Comp Inc., Hudson, Ohio, ISBN0-916589-36-6, or in any of the references cited herein, or bymonitoring the progression or severity of the underlying conditionaccording to known methods, e.g., J. B. Peter, editor, Use andInterpretation of Laboratory Tests in Infectious Disease, 5^(th)Edition, pages 1-309, 1998, Specialty Laboratories, Santa Monica,Calif., ISBN 1-889342-13-0.

Although the forgoing combination therapies have been described in thecontext of viral or other infections, the protocols and methods thatemploy a F1C can be used in conjunction with any suitable new or knowntherapeutic agent(s) or treatment protocol(s) for other any otherclinical condition described herein. Any of these additional treatmentscan be coupled with the administration of any of the F1Cs in any of theembodiments described herein. Exemplary conditions include one or moreof a non-viral pathogen infection(s), a cancer(s), a precancer(s), aninflammation condition(s), an autoimmune condition(s), animmunosuppression condition(s), a neurological disorder(s), acardiovascular disorder(s), a neurological disorder(s), diabetes,obesity, wasting, anorexia, anorexia nervosa, a cancer chemotherapy(ies)side-effect(s), a side-effect(s) of a chemotherapy(ies) or a radiationtherapy(ies) of any other clinical condition disclosed herein or in thecited references, or the like. Thus, invention embodiments include theuse of a F1C before, during or after a treatment that uses anothersuitable therapeutic agent(s) or therapeutic treatment(s) for any of thediseases or conditions disclosed herein, any of which diseases orconditions may be acute, chronic, severe, mild, moderate, stable orprogressing.

Other uses for the F1C(s) include administering the compound(s) to asubject who suffers from a pathological condition(s). The treatment maytreat or ameliorate the source of the condition(s) and/or symptomsassociated with the pathological condition(s) such as infection with apathogen(s) (viruses, bacteria, fungi), a malignancy, unwanted immuneresponse, i.e., an immune response that causes pathology and/orsymptoms, e.g., autoimmune conditions or allergy or conditions such ashypoproliferation conditions, e.g., normal or impaired tissue growth, orwound healing or burn healing, or in immunosuppression conditions, e.g.,conditions characterized by an absence of a desired response and/or aninadequate degree of a desired response.

Cancer and hyperproliferation conditions. Many cancers, precancers,malignancies or hyperproliferation conditions are associated with anunwanted Th2 immune response, a deficient Th1 response or unwantedinflammation. An insufficient Th1 immune response may play a role in thecapacity of malignant or premalignant cells to escape immunesurveillance. Any of the F1Cs disclosed herein, may thus be used totreat, prevent or slow the progression of one or more cancers,precancers or cell hyperproliferation conditions or they may be used toameliorate one or more symptoms thereof. In these conditions, the F1Csare useful to enhance the subject's Th1 responses or to reestablish amore normal Th1-Th2 balance in the subject's immune responses. The F1Csmay function at least in part by decreasing inflammation or inflammationassociated markers such as IL-6 and/or by enhancing hematopoiesis inmany of these conditions.

These conditions include cancers or precancers comprising carcinomas,sarcomas, adenomas, blastoma, disseminated tumors and solid tumors suchas one associated with or arising from prostate, lung, breast, ovary,skin, stomach, intestine, pancreas, neck, larynx, esophagus, throat,tongue, lip, oral cavity, oral mucosa, salivary gland, testes, liver,parotid, biliary tract, colon, rectum, cervix, uterus, vagina, pelvis,endometrium, kidney, bladder, central nervous system, glial cell,astrocyte, squamous cell, blood, bone marrow, muscle or thyroid cells ortissue. The F1Cs are thus useful to treat, prevent, slow the progressionof, or ameliorate one or more symptoms of a precancer, cancer or relatedhyperproliferation condition such as myelodysplastic syndrome, actinickeratoses, endometriosis, Barrett's esophagus, leiomyoma, fibromyoma,benign or precancerous intestinal or bowel polyps or benign prostatichyperplasia. The compounds can also be used to treat, prevent, slow theprogression of, slow the replication or growth of, or to ameliorate oneor more symptoms of a primary tumor, a metastasis, an advancedmalignancy, a blood born malignancy, a leukemia or a lymphoma. Any ofthese conditions may be in an early or mild form or can be moderate oradvanced in the existent or progression of the disease or a symptom.

In treating endometriosis, the use of an F1C will slow the rate ofdisease progression and decrease the severity or frequency of one ormore symptoms such as irregular menstrual periods, infertility abdominalpain or cramping and pain in the lower back or pelvic area, which mayprecede menstruation or may accompany sexual intercourse or bowelmovements. Beneficial effects from F1C treatment will be mediated inpatients with endometriosis at least partially by increasing thepatient's Th1 immune responses and/or by decreasing anti-endometrialantibodies or aberrent Th2 immune responses. Treatment of emdometriosiscould be accompanied by other suitable treatments, e.g., treatment withone or more of estrogen, progesterone, danazol, follicle stimulatinghormone antagonists, leutinizing hormone antagonists,gonadotropin-releasing hormone antagonists such as nafarelin acetate oranalgesics such as codeine, tylenol or aspirin.

The F1Cs can be used to treat paraneoplastic syndromes or conditionssuch as ones associated with lung or breast cancers that secretecalcitonin or that enhance osteoclast activity. Such conditions includehypercalcemia, Cushing's syndrome, acromegaly and non-islet cell tumorhypoglycemia. The compounds are used to decrease osteoclast activity orother symptoms associated with such conditions.

Hyperproliferation conditions that can be treated include melanoma,Kaposi's sarcoma, leiomyosarcoma, non-small cell lung cancer, small celllung cancer, bronchogenic carcinoma, renal cell cancer or carcinoma,glioma, glioblastoma, pancreatic or gastric adenocarcinoma,gastrointestinal adenocarcinoma, human papillomavirus associatedcervical intraepithelial neoplasia, cervical carcinoma, hepatoma,hepatocellular carcinoma, hepatocellular adenoma, cutaneous T-celllymphoma (mycosis fungoides, Sezary syndrome), colorectal cancer,chronic lymphocytic leukemia, chronic myelogenous leukemia, ALL orfollicular lymphoma, multiple myeloma, carcinomas with p53 mutations,colon cancer, cardiac tumors, adrenal tumors, pancreatic cancer,retinoblastoma, a small cell lung cancer, a non-small cell lung cancer,intestinal cancer, testicular cancer, stomach cancer, neuroblastoma,neuroma, myxoma, myoma, endothelioma, osteoblastoma, osteoclastoma,osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer,Kaposi's sarcoma, ovarian cancer, squamous cell carcinoma of thegastrointestinal tract and non-myeloid tumors. Treating a subject with aF1C can ameliorate one or more side effects of chemotherapy or cancersymptoms such as alopecia, pain, fever, malaise, chronic fatigue andcachexia or weight loss. Other cancers, precancers or their symptomsthat can be treated, prevented or ameliorated are described in, e.g.,Holland•Frei Cancer Medicine ^(e.)5, 5^(th) edition, R. C. Bast et al.,editors, 2000, ISBN 1-55009-113-1, pages 168-2453, B.C. Becker Inc.Hamilton, Ontario, Canada or The Merck Manual, 17^(th) edition, M. H.Beers and R. Berkow editors, 1999, Merck Research Laboratories,Whitehouse Station, N.J., ISBN 0911910-10-7.

In some of these embodiments, the subject's hyperproliferation ormalignant condition may be associated with or caused by one or morepathogens. Such conditions include hepatocellular carcinoma associatedwith HCV or HBV, Kaposi's sarcoma associated with HIV-1 or HIV-2, T cellleukemia associated with HTLV I, Burkitt's lymphoma associated withEpstein-Barr virus or papillomas or carcinoma associated with papillomaviruses (e.g., human HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 45) orgastric adenocarcinoma, gastric MALT lymphoma or gastric inflammationassociated with Helicobacter pylori, lactobacillus, enterobacter,staphylococcus or propionibacteria infection.

In some of these embodiments, the F1Cs may be used to treat, prevent orslow the progression of or ameliorate one or more conditions in asubject having or subject to developing a hyperproliferation conditionwhere angiogenesis contributes to the pathology. Abnormal or unwantedangiogenesis or neovascularization contributes to the development orprogression of solid tumor growth and metastases, as well as toarthritis, some types of eye diseases such as diabetic retinopathy,retinopathy of prematurity, macular degeneration, corneal graftrejection, neovascular glaucoma, rubeosis, retinoblastoma, uvietis andpterygia or abnormal blood vessel growth of the eye, and psoriasis. See,e.g., Moses et al., Biotech. 9:630-634 1991, Folkman et al., N. Engl. J.Med., 333:1757-1763 1995, and Auerbach et al., J. Microvasc. Res.29:401-411 1985.

Dosages of the F1C, routes of administration and the use of combinationtherapies with other standard therapeutic agents or treatments could beapplied essentially as described above for cancer or hyperproliferationconditions or other conditions as disclosed herein. Thus, in someembodiments, the use of the F1C is optionally combined with one, two ormore additional therapies for a cancer or precancer(s), e.g., one, twoor more of surgery and treatment with an antiandrogen or an antiestrogenas described herein or in the cited references, an antineoplastic agentsuch as an alkylating agent, a nitrogen mustard, a nitrosourea, anantimetabolite, a cytotoxic agent, a cytostatic agent, platinum agents,anthracyclines, taxanes or treatment with an analgesic such aspropoxyphene napsylate, acetaminophen, morphine or codeine. Exemplaryanticancer and adjunct agents include tamoxifen, paclitaxel, taxol,docetaxil, methotrexate, vincristine, vinblastine, 5-fluorouracil,thioguanine, mercaptopurine, adriamycin, chlorambucil, cyclophosphamide,cisplatin, carboplatin, transplatinum, irinotecan, procarbazine,hydroxyurea, erythropoietin, G-CSF, bicalutamide, anastrozole,fludarabine phosphate, doxorubicin and any suitable form of any of theseagents, e.g., salts and solvates. Such therapies would be usedessentially according to standard protocols and they would precede, beessentially concurrent with and/or follow treatment with a F1C. In someembodiments, such additional therapies will be administered at the sametime that a F1C is being used or within about 1 day to about 16 weeksbefore or after at least one round of treatment with the F1C iscompleted. In other embodiments, a course of therapy is administered tothe subject, e.g., treatment with a myelosuppressive amount of amyelosuppressive agent such as 5-fluorouracil, cyclophosphamide or aplatinum compound such as cisplatin, followed within about 1, 2, 3, 4, 5or 6 days by administration of one or more courses of treatment with aF1C. Other suitable exemplary therapeutic agents and their use have beendescribed in detail, see, e.g., Physicians Desk Reference 54^(th)edition, 2000, pages 303-3250, ISBN 1-56363-330-2, Medical EconomicsCo., Inc., Montvale, N.J. One or more of these exemplary agents can beused in combination with a F1C to ameliorate, slow the establishment orprogression of, prevent or treat any of the appropriate cancers,precancers or related conditions described herein, or any of theirsymptoms.

In treating cancers or hyperproliferation conditions, the F1Cs maydetectably modulate, e.g., decrease or increase, the expression or levelor activity of one or more biomolecules associated with the prevention,establishment, maintenance or progression of the cancer orhyperproliferation condition. Such biomolecules include one or more ofcarcinoembryonic antigen, prostate specific antigen, her2/neu, Bcl-XL,bcl-2, p53, IL-1α, IL-1β, IL-6, or TNFα, GATA-3, COX-2, NFκB, IkB, anIkB kinase, e.g., IkB kinase-α, IkB kinase-β or IkB kinase-γ, NFAT,calcineurin, calmodulin, a ras protein such as H-ras or K-ras, cyclin D,cyclin E, xanthine oxidase, or their isoforms, orthologs, homologs ormutant forms, which may be observed as either reduced or increasedlevels or biological activity(ies). Biomolecule levels or theiractivity(ies) that can be at least transiently detectably increasedinclude one or more IL-2, IFNγ, IL-12, T-bet,O6-methylguanine-DNA-methyltransferase, calcineurin, calmodulin, asuperoxide dismutase (e.g., Mn, Zn or Cu), a tumor suppressor proteinsuch as the retinoblastoma protein (Rb) or CDKN2A (p16), BRCA1, BRCA2,MeCP2, MBD2, PTEN, NBR1, NBR2 or the isoforms, orthologs, homologs ormutant forms, which may have either attenuated or enhanced biologicalactivity(ies), of any of these molecules. In treating a cancer describedherein such as prostate cancer, one or more of ELAC2,2′,5′-oligoadenylate dependent RNAse L (RNASEL), macrophage scavengerreceptor 1 (MSR1), BRCA2 can be modulated or decreased.

The F1Cs can modulate the synthesis or a biological activity of one ormore other gene products such as transcription factors, enzymes orsteroid or other receptors that are associated with the establishment,progression or maintenance of a cancer or precancer or associatedsymptom. The compounds can inhibit AIB-1 coactivator or HER2/neusynthesis or activity in breast cancer cells or breast cancerconditions. They can enhance the synthesis or an activity of an estrogenreceptor such as ERα, ERβ1 or ERβ2 or progesterone receptor in breastcancer or colon cancer cells or conditions. These effects can includemodulation of the expression or one or more biological activities ofproteins or enzymes that contribute to disease establishment orprogression. Thus, the compounds can decrease IL-4, IL-6 or IL-13expression by stromal cells or immune cells that are in proximity to oradjacent to solid or diffuse tumor cells in a subject such as a human oranother mammal. In the cancers or precancers described herein, thecompounds can thus directly or indirectly modulate (e.g., decrease) theactivity or expression of relevant enzymes such as STAT-6, neutralendopeptidase, a hydroxysteroid dehydrogenase, such as a17β-hydroxysteroid dehydrogenase, 11β-hydroxysteroid dehydrogenase,7β-hydroxysteroid dehydrogenase or a 3β-hydroxysteroid dehydrogenase.

In some embodiments, the F1Cs are used to treat tumors or cancerswherein proliferation of the tumor or cancer cells is enhanced inresponse to sex steroids such as natural or synthetic androgens orestrogens. In other embodiments, the tumor or cancer cells are notresponsive to such hormones or they are only slightly responsive to thepresence of such compounds.

Cardiovascular applications. Any of the F1Cs disclosed herein, may beused to treat, prevent or slow the progression of one or more ofcongenital heart defects, cardiovascular diseases, disorders,abnormalities and/or conditions, or to ameliorate one or more symptomsthereof in a subject. These include peripheral artery disease,arterio-arterial fistula, arteriovenous fistula, cerebral arteriovenousmalformations, aortic coarctation, cor triatum, coronary vesselanomalies, patent ductus arteriosus, Ebstein's anomaly, hypoplastic leftheart syndrome, levocardia, transposition of great vessels, doubleoutlet right ventricle, tricuspid atresia, persistent truncusarteriosus, and heart septal defects, such as aortopulmonary septaldefect, endocardial cushion defects, Lutembacher's Syndrome, ventricularheart septal defects, cardiac tamponade, endocarditis (includingbacterial), heart aneurysm, cardiac arrest, congestive heart failure,congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema,post-infarction heart rupture, ventricular septal rupture, heart valvediseases, myocardial diseases, pericardial effusion, pericarditis(including constrictive and tuberculous), pneumopericardium,postpericardiotomy syndrome, pulmonary heart disease, rheumatic heartdisease, ventricular dysfunction, hyperemia, cardiovascular pregnancycomplications, cardiovascular syphilis, cardiovascular tuberculosis,arrhythmias such as sinus arrhythmia, atrial fibrillation, atrialflutter, bradycardia, extrasystole, Adams-Stokes Syndrome, bundle-branchblock, sinoatrial block, long QT syndrome, parasystole, sick sinussyndrome, ventricular fibrillations, tachycardias such as paroxysmaltachycardia, supraventricular tachycardia, accelerated idioventricularrhythm, atrioventricular nodal reentry tachycardia, ectopic atrialtachycardia, ectopic junctional tachycardia, sinoatrial nodal reentrytachycardia, sinus tachycardia, Torsades de Pointes, and ventriculartachycardia and heart valve diseases such as aortic valve insufficiency,aortic valve stenosis, hear murmurs, aortic valve prolapse, mitral valveprolapse, tricuspid valve prolapse, mitral valve insufficiency, mitralvalve stenosis, pulmonary atresia, pulmonary valve insufficiency,pulmonary valve stenosis, tricuspid atresia, tricuspid valveinsufficiency, and tricuspid valve stenosis.

The F1Cs can be used to treat, prevent or ameliorate one or moresymptoms of myocardial diseases or pathological myocardial or vascularconditions such as alcoholic cardiomyopathy, congestive cardiomyopathy,hypertrophic cardiomyopathy, aortic subvalvular stenosis, pulmonarysubvalvular stenosis, restrictive cardiomyopathy, Chagas cardiomyopathy,endocardial fibroelastosis, myocardial fibrosis, endomyocardialfibrosis, Kearns Syndrome, myocardial reperfusion injury, myocarditis,cardiovascular or vascular diseases such as dissecting aneurysms, falseaneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms,cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliacaneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis,Sturge-Weber Syndrome, angioneurotic edema, aortic diseases, Takayasu'sArteritis, aortitis, Leriche's Syndrome, arterial occlusive diseases,arteritis, enarteritis, polyarteritis nodosa, cerebrovascular diseases,disorders, and/or conditions, diabetic angiopathies, diabeticretinopathy, thrombosis, erythromelalgia, hemorrhoids, hepaticveno-occlusive disease, hypertension, hypotension, idiopathic pulmonaryfibrosis, peripheral vascular diseases, phlebitis, pulmonaryveno-occlusive disease, Raynaud's disease, CREST syndrome, retinal veinocclusion, Scimitar syndrome, superior vena cava syndrome,telangiectasia, atacia telangiectasia, hereditary hemorrhagictelangiectasia, varicocele, varicose veins, varicose ulcer, vasculitis,venous insufficiency and arterial occlusive diseases such asarteriosclerosis, intermittent claudication, carotid stenosis,fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoyadisease retinal artery occlusion, thromboangiitis obliterans oratherosclerosis, any of which may be at an early stage or at a moreadvanced or late stage.

The F1Cs can also be used to treat, prevent or ameliorate one or moresymptoms of cerebrovascular diseases, thrombosis, and/or conditions suchas carotid artery diseases, cerebral amyloid angiopathy, cerebralaneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebralarteriovenous malformation, cerebral artery diseases, cerebral embolismand thrombosis, carotid artery thrombosis, sinus thrombosis,Wallenberg's syndrome, cerebral hemorrhage, epidural hematoma, subduralhematoma, subarachnoid hemorrhage, cerebral infarction, cerebralischemia (including transient), subclavian steal syndrome,periventricular leukomalacia, vascular headache, cluster headache,migraine, vertebrobasilar insufficiency, air embolisms, embolisms suchas cholesterol embolisms, fat embolisms, pulmonary embolisms or amnioticfluid embolism, thromoboembolisms, thrombosis such as coronarythrombosis, hepatic vein thrombosis, retinal vein occlusion, carotidartery thrombosis, sinus thrombosis, Wallenberg's syndrome, andthrombophlebitis.

The F1Cs can also be used to treat, prevent or ameliorate one or moresymptoms of vascular ischemia or myocardial ischemias, vasculitis andcoronary diseases, including angina pectoris, coronary aneurysm,coronary arteriosclerosis, coronary thrombosis, coronary vasospasm,myocardial infarction and myocardial stunning, cerebral ischemia,ischemic colitis, compartment syndromes, anterior compartment syndrome,myocardial ischemia, reperfusion injuries, peripheral limb ischemia,aortitis, arteritis, Behcet's Syndrome, mucocutaneous lymph nodesyndrome, thromboangiitis obliterans, hypersensitivity vasculitis,Schoenlein-Henoch purpura, allergic cutaneous vasculitis, Wegener'sgranulomatosis or metabolic syndrome, which may be accompanied by one,two or more of obesity, insulin resistance, dyslipidemia, hypertensionor other related symptoms or conditions.

Exemplary symptoms that the use of the F1Cs can ameliorate include oneor more of pain such as arm, jaw or chest pain, edema or swelling, highblood pressure, shortness of breath or dyspnea, e.g., on exertion orwhile prone, fatigue or malaise and low cardiac injection fraction. Intreating a cardiovascular condition in a subject or in improving one ormore symptoms thereof, the F1Cs may accomplish one or more of increasingcardiac ejection volume or fraction, decreasing levels of IL-6,decreasing levels of C reactive protein, fibrinogen, cardiac creatininekinase, increasing fatty acid metabolism or utlization by cardiactissue, increasing carnityl palmitoyl fatty acid transferase or othercardiac metabolic enzymes, activating potassium dependent calciumchannels, vasodilating or enhancing oxygen delivery to ischemic tissuesor decreasing levels of scarring or plaque formation that occurs, e.g.,after vascular damage. Symptoms associated with a cardiovascularcondition such as ischemia that can be ameliorated also includeacidosis, expression of one or more immediate early genes in, e.g.,glial cells, vascular smooth muscle cells or endothelial cells, neuronalmembrane depolarization and increased neuronal extracellular calcium andglutamate concentration. Other biological effects associated withtreatment using a F1C may also be monitored, e.g., and increase ordecrease of a cell surface antigen, a cytokine or an interleukin asdisclosed herein.

Useful biological effects of the F1Cs in cardiovascular indications suchas myocardial ischemias also include preventing or reducing heart orvascular cell death and subsequent fibrosis. These effects areassociated with a decreased oxidative capacity of heart cells ormyocytes, which is associated with a decreased capacity of the cells tometabolize fatty acids efficiently. The compounds enhance fatty acidmetabolism and ameliorate the deleterious effects of a limited oxidativecapacity.

The F1Cs also can limit inflammation or cell injury that is associatedwith ischemia or oxygen reperfusion after ischemia. Ischemia, which is adetrimental decrease in oxygenated blood delivery to affected cells ortissues, may arise from a cardiovascular condition or event such as aninfarction, or from thermal injury or burns. Ischemia may also arisefrom accidental or surgical trauma. Reperfusion after cells have becomehypoxic for a sufficient period of time can lead to tissue or cellinjury that varies from slight to lethal. The compounds can reduce cellor tissue injury or death associated with ischemia and reperfusion, by,e.g., reducing inflammation or the level of a molecule associated withinflammation. Thus, levels of a proinflammatory cytokine or moleculesuch as leukotriene B4, platelet activating factor or levels ofextracellular P-selectin may result from administration of a F1C to asubject who may experience reperfusion injury. Thus, the compounds canreduce injury or death of, e.g., neuron, cardiac, vascular endothelium,myocardial, pulmonary, hepatic or renal cells or tissues. Withoutwishing to be bound by any theory, the compounds may act in part byreducing one or more of neutrophil activation, platelet activation,platelet aggregation, endothelial cell activation and neutrophiladherence or adhesion to endothelial cells in these conditions.

The F1Cs are useful to treat autoimmune or metabolic conditions ordisorders, or their symptoms, in subjects such as mammals or humans,that relate to impaired insulin synthesis or use or that relate toabnormal or pathological lipid or cholesterol metabolism or levels. Suchconditions and symptoms include polycystic ovarian syndrome, Type 1diabetes (including Immune-Mediated Diabetes Mellitus and IdiopathicDiabetes Mellitus), Type 2 diabetes (including forms with (1)predominant or profound insulin resistance, (2) predominant insulindeficiency and some insulin resistance, (3) forms intermediate betweenthese), obesity, hyperglycemia and dyslipidemia, unwanted hyperlipidemiaconditions such as hypertriglyceridemia and hypercholesterolemias suchas hyper-LDL cholesterolemia, (4) unwanted hypolipidemias, e.g.,hypo-HDL cholesterolemia or low HDL cholesterol levels and (5) anginapectoris. In diabetes, the compounds are useful to (1) enhance β-cellfunction in the islets of Langerhans (e.g., increase insulin secretion),(2) reduce the rate of islet cell damage, (3) increase insulin receptorlevels or activity to increase cell sensitivity to insulin and/or (4)modulate glucocorticoid receptor activity to decrease insulin resistancein cells that are insulin resistant. The compounds are thus useful totreat, prevent, ameliorate or slow the progression of a metabolic orcardiovascular condition such as diabetes or hyperglycemia, or a relatedsymptom or condition such as a dyslipidemia in a subject such as a humanor a mammal.

Beneficial effects that can the F1Cs can exert on such related symptomsor conditions include improved glucose tolerance, improved glucoseutilization, decreased severity or slowed progression of vasculardisease (e.g., microvascular or macrovascular disease, includingnephropathy, neuropathy, retinopathy, hypertension, cerebrovasculardisease and coronary heart disease) or a decreased severity or slowedprogression of atherosclerosis, an arteriosclerosis condition (e.g.,coronary arteriosclerosis, hyperplastic arteriosclerosis, peripheralarteriosclerosis or hypertensive arteriosclerosis), decreased severityor slowed progression of diabetic osteoarthropathy, skin lesions,rhabdomyolysis, ketosis, detectably decreased generation of islet cellautoantibodies, decreased levels or activity of inflammatory macrophages(foam cells) in atherosclerotic plaques, or detectably decreasedexpression or levels of one or more of human (or mammalian)angiopoietin-like 3 gene product, apolipoprotein C-1, inducible orconstitutive nitric oxide synthase, e.g., in endothelial cells,macrophages or the like, pyruvate dehydrogenase kinase 4, carboxyl esterlipase, cholesteryl ester transfer protein, endothelial lipase, vascularwall lipoprotein lipase, anti-lipoprotein lipase autoantibodies,triglyceride-rich lipoproteins, LDL cholesterol, C-reactive protein,high sensitivity C-reactive protein, fibrinogen, plasma homocysteine,VCAM-1, IL-1 (e.g., IL-1β), IL-6, a TNF (e.g., TNFα), AP-1, NF-κB, andIFN-γ. In these any of these diseases or conditions, the F1Cs can alsomodulate, e.g., detectably increase, the activity or level of one, twoor more of human (or mammalian) LOX-1, apolipoprotein A-1,apolipoprotein A-2, LPDL lipase, hormone sensitive lipase, paraoxonase,brain natriuretic peptide, a brain natriuretic peptide receptor, e.g.,Npr1 or Npr3, hepatic lipase, LDL receptor, HDL apoliporpotein E, HDLapoliporpotein J, HDL cholesterol, VLDL receptor, ATP-binding casettetransporter 1, leukemia inhibitory factor, CD36, LXRα, LXRβ, CARβ, RXR,PPARα, PPARβ, PPARγ or a lipoprotein lipase, e.g., marophage lipoproteinlipase. As used herein, obesity includes a human with a body mass indexof at least about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 orgreater. Obese humans that are treated with a F1C may have one or moreof the conditions described here.

The F1Cs are useful in treating insulin resistance and associatedsymptoms and conditions. Insulin resistance is typically observed as adiminished ability of insulin to exert its biological action across abroad range of concentrations. This leads to less than the expectedbiologic effect for a given level of insulin. Insulin resistant subjectsor human have a diminished ability to properly metabolize glucose orfatty acids and respond poorly, if at all, to insulin therapy.Manifestations of insulin resistance include insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. Insulin resistance can causeor contribute to polycystic ovarian syndrome, impaired glucosetolerance, gestational diabetes, hypertension, obesity, atherosclerosisand a variety of other disorders. Insulin resistant individuals canprogress to a diabetic state. The compounds can also be used in thetreatment or amelioration of one or more condition associated withinsulin resistance or glucose intolerance including an increase inplasma triglycerides and a decrease in high-density lipoproteincholesterol, high blood pressure, hyperuricemia, smaller denserlow-density lipoprotein particles, and higher circulating levels ofplasminogen activator inhibitor-1. Such diseases and symptoms have beendescribed, see, e.g., G. M. Reaven, J. Basic Clin. Phys. Pharm. 1998, 9:387-406, G. M. Reaven, Physiol. Rev. 1995, 75: 473-486 and J. Flier, J.Ann. Rev. Med. 1983, 34:145-60.

The compounds can thus be used in diabetes, obesity, hyperlipidemia orhypercholesterolemia conditions to reduce body fat mass, increase musclemass or to lower one or more of serum or blood low density lipoprotein,triglyceride, cholesterol, apolipoprotein B, free fatty acid or very lowdensity lipoprotein compared to a subject that would otherwise beconsidered normal for one or more of these characteristics. Thesebeneficial effects are typically obtained with little or no effect onserum or blood high density lipoprotein levels. The F1Cs are useful toreduce or slow the rate of myocardial tissue or myocyte damage, e.g.,fibrosis, or to enhance cardiac fatty acid metabolism in conditions,such as inflammation, where fatty acid metabolism is depressed ordecreased. Elevated cholesterol levels are often associated with anumber of other disease states, including coronary artery disease,angina pectoris, carotid artery disease, strokes, cerebralarteriosclerosis, and xanthoma, which the F1Cs can ameliorate or slowthe progression or severity of. Abnormal lipid and cholesterolconditions that can be treated include exogenous hypertriglyceridemia,familial hypercholesterolemia, polygenic hypercholesterolemia, biliarycirrhosis, familial combined hyperlipidemia, dysbetalipoproteinemia,endogenous hypertriglyceridemia, mixed hypertriglyceridemia andhyperlipidemia or hypertriglycidemia secondary to alcohol consumption,diabetic lipemia, nephrosis or drug treatments, e.g., corticosteroid,estrogen, colestipol, cholestyramine or retinoid treatments. Dosages,routes of administration and dosing protocols for the F1Cs areessentially as described herein. Where the condition is chronic, theF1Cs will generally be administered to a subject such as a human for arelatively long time period, e.g., for about 3 months to about 10 yearsor more. Dosages, routes of administration and dosing protocols for theF1Cs are essentially as described herein. Dosing of the compound can bedaily or intermittent using a dosing protocol using dosages as describedherein, e.g., about 0.01 to about 20 mg/kg of a F1C administered to asubject once or twice per day daily or intermittently. The use of theF1Cs can be combined with one, two or more other suitable treatments,e.g., treatment for cessation of smoking, diet control, e.g., caloricrestriction or reduced fat intake, or treatment with fibrates,non-steroidal anti-inflammatory drugs, angiotensin-converting enzymeinhibitors or HMG-CoA reductase inhibitors such as aspirin, clofibrate,fenofibrate, ciprofibrate, gemfibrozil, Simvastatin™, Pravastatin™,Mevastatin™ or Lovastatin™.

The use of any F1C or species in any genus of F1Cs disclosed herein totreat, prevent or ameliorate any of these cardiovascular or metabolicdisorders or symptoms will generally use one or more of the routes ofadministration, dosages and dosing protocols as disclosed herein. Thus,in exemplary embodiments, about 0.5 to about 100 mg/kg or about 1 toabout 25 mg/kg, of the F1C will be administered per day by an oral,buccal, sublingual or parenteral route. Such administration can be,e.g., daily for about 5 to about 60 days in acute conditions or it canbe intermittent for about 3 months to about 2 years or more for chronicconditions. Alternatively, intermittent dosing can be used essentiallyas described herein for acute cardiovascular conditions. In someembodiments, for conditions such as ischemia or trauma, administrationof the F1C is provided before or as soon after the ischemic or traumaticevent as possible, e.g., within about 6 hours of an ischemic ortraumatic event or about 12-24 hours before an anticiapted ischemic ortraumatic event. In other embodiments, administration of the F1C can bedelayed for, e.g., about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19,20, 21, 24, 28, 32, 36, 40, 48 or more hours after an ischemic ortraumatic event has occurred and a course of daily or intermittentdosing is initiated of one of these times, or in a range between any ofthese times after the event. Thus, administration of the F1C can beginat about 10-14 hours, at about 11-13 hours or at about 8-16 hours afterthe ischemic or traumatic event.

In another aspect of the invention, the F1Cs can be used to prevent,treat or to reduce the severity of vascular or microvascular occlusionsin human sickle cell diseases (SCD). SCD is heterogenous and includessubgroups with high transcranial velocities, which is a group with anincreased risk of infarctive stroke or cereberal thrombosis. SCD typesalso include sickle cell-β⁺ thalassemia, sickle cell-β^(◯) thalassemia,sickle cell-δβ^(◯) thalassemia and sickle cell-HPFH (hereditary ofpersistent fetal hemoglobin). Another subgroup of SCD patients ischaracterized by the presence of a Plasmodium parasite infection. SCD isusually accompanied by acute vaso-occlusive episodes such asmicrovascular occlusions, ischemia and infarctions that arise fromadhesion of sickle cells and other blood cell types, e.g., platelets orleukocytes, to vascular endothelial cells. Reduced sickle cell adhesionin response to treatment with a F1C and related responses is facilitatedat least in part by decreased production or activity of one or morebiological response mediators such as one, two, three or more ofthrombospondin, von Willebrand factor, epinephrine, C reactive protein,cAMP, basal cell adhesion molecule/Lutheran (BCAM/Lu), P-selectin,L-selectin, E-selectin, VCAM-1, ICAM-1, fibronectin, annexin V, placentagrowth factor, superoxide, CD11a, CD11b, CD11c, CD15, CD18, CD31, CD36,TNFα, NF-κB, IL-1β or IL-6 by endothelial cells or one or more immunecell types as described herein. In treating sickle cell disease, theF1Cs will also increase the activity or levels of one, two or moredesired response mediators including fetal hemoglobin, erythropoietin,heme oxygenase, nitric oxide, PPARα, PPARγ or GM-CSF. The F1Cs will thusameliorate one or more symptoms of sickle cell disease such as anemia,stroke, pain, e.g., chest or abdominal pain, skin ulcers, dyspnea, organdamage, retinopathy or the level of infected red cells inPlasmodium-infected subjects. Treatment of acute SCD episodes or ofchronic SCD with F1Cs can be combined with other suitable therapies,e.g., inhaled nitric oxide, hydroxyurea treatment, anti-adhesionmolecule antibody treatment or analgesic use such as morphine,oxycodone, or codeine. The F1Cs can also be used to reduce cellulardamage from reactive oxygen species associated with hydroxyureatreatment, since the F1Cs will enhance cellular antioxidant capacity.

As is apparent from the foregoing, the use of the F1C is optionallycombined with one or more additional therapies for cardiovascular orrelated disorders, e.g., insulin therapy, vascular surgery, cardiacsurgery, angioplasty, or treatment with andrenergic blockers, coronaryvasodilators, calcium channel blockers, nitrates, angiotensin convertingenzyme inhibitors, anti-hypertensives, anti-inflammatory agents,diuretics, anti-arrhythmia agents, thrombolytic agents, enzymeinhibitors such as hydroxymethylglutaryl CoA reductase inhibitors orxanthine oxidase inhibitors. Exemplary hydroxymethylglutaryl CoAreductase inhibitors include statins such as mevastatin, lovastatin,pravastatin, simvastatin or compounds described in U.S. Pat. No.4,346,227, 4,448,979, 4,739,073, 5,169,857, 5,006,530 or 5,401,746.Other therapies that can be applied include diet control, dietarycalorie restriction or diet modification for subjects who are or who aresusceptible to developing a cardiovascular or related condition such aspulmonary hypertension, diabetes, a dyslipidemia or obesity, e.g.,humans having a body mass index of 27, 28, 29, 30, 31, 32, 33, 34, 35,36 or greater. Diet modifications include limiting or restricting salt,alcohol, caffeine, cigarette, drugs, e.g., opiate, hallucinogen,sedative, narcotic or amphetamine, sugar, refined sugar and/or fat orcholesterol intake, use or abuse. Additional therapies include treatmentwith one or more of digoxin, nitroglycerin, doxazosin mesylate,nifedipine, enalapril maleate, indomethicin, tissue plasminoginactivator, urokinase, acetylsalicylic acid or the like. Any of suchadditional therapies would be used essentially according to standardprotocols and such therapies would precede, be concurrent with or followtreatment with a F1C. In some embodiments, such additional therapieswill be administered at the same time that a F1C is being used or withinabout 1 day to about 16 weeks before or after at least one round oftreatment with the F1C is completed. Other exemplary therapeutic agentsand their use have been described in detail, see, e.g., Physicians DeskReference 54^(th) edition, 2000, pages 303-3251, ISBN 1-56363-330-2,Medical Economics Co., Inc., Montvale, N.J.; Harrison's Principles ofInternal Medicine, 15^(th) edition, 2001, E. Braunwald, et al., editors,McGraw-Hill, New York, N.Y., ISBN 0-07-007272-8, especially chapters231, 241-248 and 258-265 at pages 1309-1318, 1377-1442 and 1491-1526.One or more of these exemplary agents or treatments can be used incombination with a F1C to treat any of the appropriate cardiovascularand related disorders described herein and in the references citedherein.

Respiratory and pulmonary conditions. F1Cs can be used to treat,ameliorate, prevent or slow the progression of a number of pulmonaryconditions or their symptoms such as 1, 2, 3 or more of cystic fibrosis,bronchiectasis, cor pulmonale, pneumonia, lung abcess, acute bronchitis,chronic bronchitis, chronic obstructive pulmonary diseases, emphysema,pneumonitis, e.g., hypersensitivity pneumonitis or pneumonitisassociated with radiation exposure, alveolar lung diseases andinterstitial lung diseases, e.g., associated with asbestos, fumes or gasexposure, aspiration pneumonia, pulmonary hemorrhage syndromes,amyloidosis, connective tissue diseases, systemic sclerosis, ankylosingspondylitis, allergic granulomatosis, granulomatous vasculitides,asthma, e.g., acute asthma, chronic asthma, atopic asthma, allergicasthma or idiosyncratic asthma, cystic fibrosis and associatedconditions, e.g., allergic bronchopulmonary aspergillosis, chronicsinusitis, pancreatic insufficiency, inflammation or Haemophilusinfluenzae, S. aureus or Pseudomonas aeruginosa infection. In some ofthese conditions where inflammation plays a role in the pathology of thecondition, the F1Cs can ameliorate or slow the progression of thecondition by reducing damage from inflammation. In other cases, the F1Csact to limit pathogen replication or pathogen-associated lung tissuedamage.

For these conditions, the severity of the disease or the type orseverity of associated symptoms can vary. For example, in humans havingpediatric, e.g., infants or children of about 1 month or about 4 monthsof age to about 16 or 17 years of age, or adult cystic fibrosis (“CF”),the disease may be associated with the presence of one or more symptoms,syndromes, genetic mutations or the like. Symptoms or syndromes that canbe observed in human CF patients include 1, 2, 3, 4 or more ofStaphylococcus (e.g., S. aureus), Haemophilus influenzae, Pseudomonas orBurkholderia respiratory tract or lung infection or propensity todevelop detectable infection or colonization, coughing, wheezing,cyanosis, bronchiolitis, bronchospasm, pneumothorax, hemoptysis,pancreatic exocrine insufficiency, bronchiectatic lung disease,atelectasis-consolidation, pulmonary edema, increased lung vascularhydrostatic pressure, increased lung vascular permeability, sinusitis,respiratory insufficiency, bronchial wall or interlobular septathickening, reduction of forced expiratory volume in 1 second, dyspnea,impaired male fertility, elevated sweat chloride (e.g., >60 mmol/L),mucous plugging, tree-in-bud sign, mosaic perfusion pattern, glucoseintolerance or abnormal elevation of one or more of IL-4, IL-8, RANTES,neutrophil elastase, eosinophils, macrophages, neutrophils, eosinophilcationic protein or cysteinyl leukotrienes. Any of these symptoms orsyndromes can be acute, intermittent or chronic and/or mild, moderate orsevere. Relevant mutations include, e.g., a homozygous or heterozygous,dominant or recessive deletion, insertion and/or point mutation in (1)the cationic trypsinogen gene or (2) the cystic fibrosis transmembraneconductance regulator (CFTR) gene, such as one, two or more of, a CFTRF508del deletion mutation or CFTR lacking phe508, 3272-26A>G/F508del,3659delC, 394delTT, S1455X or Δ26, I1234V, 2183AA>G, 2043delG, 548A>T,I148T, R334W, S1196X, 4041C>G, 1161delC, 1756G>T or 3120+1G>A mutation.

The use of a F1C to treat, ameliorate or slow the progression ofconditions such as CF can be optionally combined with other suitabletreatments. For CF, this includes, e.g., one, two or more of oral oraerosol corticosteroid treatment, ibuprofen treatment, DNAse or IL-10treatment, diet control, e.g., vitamin E supplementation, vaccinationagainst pathogens, e.g., Haemophilus influenzae, or chest physicaltherapy, e.g., chest drainage or percussion.

Humans or other subjects who have one or more of these conditions can betreated with other suitable therapeutics. Pulmonary conditions that canbe treated with the F1Cs and other therapeutic methods and agents thatcan be used in conjunction with the F1Cs have been described in detail,see, e.g., Harrison's Principles of Internal Medicine, 15^(th) edition,2001, E. Braunwald, et al., editors, McGraw-Hill, New York, N.Y., ISBN0-07-007272-8, especially chapters 252-265 at pages 1456-1526;Physicians Desk Reference 54^(th) edition, 2000, pages 303-3251, ISBN1-56363-330-2, Medical Economics Co., Inc., Montvale, N.J. One or moreof these exemplary agents or treatments can be used in combination witha F1C to treat any of the appropriate cardiovascular and relateddisorders described herein and in the references cited herein. Treatmentof any of these respiratory and pulmonary conditions using a F1C isaccomplished using the treatment regimens described herein. For chronicconditions, intermittent dosing of the F1C can be used to reduce thefrequency of treatment. Intermittent dosing protocols are as describedherein.

Applications in autoimmunity, allergy, inflammation and relatedconditions. As mentioned above, the F1Cs may be used to treat, preventor slow the progression of one or more autoimmune allergic orinflammatory diseases, disorders, or conditions, or to ameliorate one ormore symptoms thereof in a subject. These diseases and conditionsinclude Addison's Disease, autoimmune hemolytic anemia, autoimmunesensorineural hearing loss, antiphospholipid syndrome, acute or chronicrheumatoid arthritis and other synovial disorders, an osteoarthritisincluding post-traumatic osteoarthritis and hypertrophic pulmonaryosteoarthropathy, psoriatic arthritis, polyarthritis, epichondylitis,type I diabetes, type II diabetes, rheumatic carditis, bursitis,ankylosing spondylitis, multiple sclerosis, a dermatitis such as contactdermatitis, atopic dermatitis, exfoliative dermatitis or seborrheicdermatitis, mycosis fungoides, allergic encephalomyelitis, autoimmuneglomerulonephritis, Goodpasture's Syndrome, Graves' Disease, Hashimoto'sThyroiditis, multiple sclerosis, myasthenia gravis, neuritis, bullouspemphigoid, pemphigus, polyendocrinopathies, purpura, Reiter's Disease,autoimmune thyroiditis, systemic lupus erythematosus, scleroderma,fibromyalgia, chronic fatigue syndrome, autoimmune pulmonaryinflammation, Guillain-Barre Syndrome, type 1 or insulin dependentdiabetes mellitus, autoimmune inflammatory eye disease, hepatitis Cvirus associated autoimmunity, postinfectious autoimmunity associatedwith, e.g., virus or bacterial infection such as a parvovirus such ashuman parvovirus B19 or with rubella virus, autoimmune skin and muscleconditions such as pemphigus vulgaris, pemphigus foliaceus, systemicdermatomyositis or polymyositis or another inflammatory myopathy,myocarditis, asthma such as allergic asthma, allergic encephalomyelitis,allergic rhinitis, a vasculitis condition such as polyarteritis nodosa,giant cell arteritis or systemic necrotizing vasculitis, chronic and anacute or chronic inflammation condition such as chronic prostatitis,granulomatous prostatitis and malacoplakia, ischemia-reperfusion injury,endotoxin exposure, complement-mediated hyperacute rejection, nephritis,cytokine or chemokine induced lung injury, cachexia, sarcoidosis,inflammatory bowel disease, regional enteritis, ulcerative colitis,Crohn's disease, inflammatory bowel disease or inflammation associatedwith an infection, e.g., septic shock, sepsis, or systemic inflammatoryresponse syndrome. Any of these diseases or conditions or their symptomsmay be acute, chronic, mild, moderate, severe, stable or progressingbefore, during or after the time administration of the F1C to a subjectsuch as a human, is initiated. In general, a detectable improvement isobserved in the subject within a period of about 3 days to about 12months after initiation of a dosing protocol, e.g., the severity of thedisease or condition will detectably decrease, the rate of progressionwill detectably slow or the severity of a symptom(s) will detectablydecrease.

As used herein, acute inflammation conditions are characterized as aninflammation that typically has a fairly rapid onset, quickly becomesmoderate or severe and usually lasts for only a few days or for a fewweeks. Chronic inflammation conditions as used herein are characterizedas an inflammation that may begin with a relatively rapid onset or in aslow, or even unnoticed manner, tends to persist for at least severalweeks, e.g., about 3-6 weeks, months, or years and may have a vague orindefinite termination. Chronic inflammation may result when theinjuring agent (or products resulting from its presence) persists in thelesion, and the subject's tissues respond in a manner (or to a degree)that is not sufficient to overcome completely the continuing effects ofthe injuring agent. Other exemplary conditions are described in, e.g.,Textbook of Autoimmune Diseases, R. G. Lahita, editor, LippincottWilliams & Wikins, Philadelphia, Pa., 2000, ISBN 0-7817-1505-9, pages175-851 and Rheumatology, 2^(nd) edition, J. H. Klippel et al., editors,1998, ISBN 0-7234-2405-5, volume 1, sections 1-5 and volume 2, sections6-8, Mosby International, London, UK.

A F1C can be used to inhibit or ameliorate one or more inappropriateimmune responses or their symptoms in autoimmunity, inflammation,allergy or related conditions. The effects of the F1Cs includedetectably ameliorating one or more of (1) the proliferation,differentiation or chemotaxis of T cells, (2) reducing unwantedcytotoxic T cell responses, (3) reducing unwanted autoantibody or otherantibody synthesis, e.g., an unwanted IgA, IgE, IgG or IgM, in allergy,asthma or another autoimmune or inflammation condition, (4) inhibitingthe development, proliferation or unwanted activity of autoreactive T orB cells, (5) altering the expression of one or more cytokines,interleukins or cell surface antigens, e.g., a cytokine, interleukin orcell surface antigen described herein (decreasing IL-8 in an autoimmunecondition, decreasing the level of acute phase proteins such as Creactive protein or fibrinogen in inflammation conditions, (6)decreasing eosinophilia in allergy conditions, (7) detectably decreasingthe level or activity of one or more of ICAM-1, IL-1α, IL-1β, TNFα, IL-6or IL-8 in, e.g., inflammation conditions or in autoimmune conditionssuch as an arthritis or a myocarditis condition such as osteoarthritis,rheumatoid arthritis, toxic myocarditis, indurative myocarditis oridiopathic myocarditis, (8) decreasing the level or biological activityof one or more of anti-islet antibody, TNF, IFN-γ, IL-1, an arthritissymptom(s), nephritis, skin rash, photosensitivity, headache frequencyor pain, migraine frequency or pain, abdominal pain, nausea or anti-DNAantibodies in, e.g., insulin dependent diabetes mellitus or anautoimmune or inflammation condition such as systemic lupuserythematosus, rheumatoid arthritis or Crohn's disease, (9) reducinginduction of arachidonic acid metabolism or reducing eicosanoidmetabolites such as thromboxanes or prostaglandins in, e.g.,inflammation, asthma or allergy, (10) reducing IL-4, IL-8 or IL-10synthesis, levels or activity in, e.g., allergy or inflammation such asidiopathic pulmonary fibrosis or allergic asthma or (11) reducing orinterfering with neutrophil chemotaxis by, e.g., reducing thioredoxinrelease from affected cells in conditions such as cancer, infections,inflammation or autoimmunity.

Exemplary symptoms that the use of the F1Cs can ameliorate in theseautoimmune, inflammatory and allergy conditions include one or more ofpain such as shoulder, hip, joint, abdominal or spine pain, jointstiffness or gelling, bursitis, tendonitis, edema or swelling, fatigueor malaise, headache, dyspnea, skin rash, fever, night sweats, anorexia,weight loss, skin or intestine ulceration, muscle weakness,pericarditis, coronary occlusion, neuropathy and diarrhea. In treatingone of these conditions in a subject or in improving one or moresymptoms thereof, the F1Cs may accomplish one or more of decreasinglevels of one or more of IL-1, IL-4, IL-6 or TNFα, decreasing levels ofC reactive protein, fibrinogen or creatinine kinase. Other biologicaleffects associated with treatment using a F1C may also be monitored orobserved, e.g., an increase or decrease of a cell surface antigen, acytokine or an interleukin as disclosed herein.

In another aspect of the invention, the F1Cs can be used to treat or toreduce the severity of chronic allergies or atopic diseases such asallergic rhinitis, psoriasis, eczema, gastrointestinal allergies, atopicdermatitis conditions, allergic asthma, food allergies and hay fever.These conditions are typically characterized by the presence of elevatedlevels of allergen specific antibodies of the IgE isotype. In treatingor ameliorating these conditions, the F1Cs reduce the generation of IgEby “isotype switching”, which is increasing allergen-specific IgAproduction and/or decreasing IgE production from preexistingallergen-primed cells. Allergen specific IgG may also be increased fromnew cells that might otherwise have responded to allergen exposure bygenerating unwanted IgE.

The IgA and IgG are allergen specific, which will enhance clearance ofallergen from mucosa or other tissue and reduction of chronic or latephase allergic responses. The F1C can thus also be used to increase thebiological clearance of allergens from tissue and mucosa. Reducedgeneration of the levels or activity of IgE by B cells in response totreatment with a F1C and related responses is facilitated at least inpart by decreased production of one or more biological responsemediators, e.g., cytokines or response mediators such as protein kinaseA inhibitors, substance P neuropeptide, thymus- and activation-regulatedchemokine, e.g., by airway smooth muscle cells, proteinase activatedreceptor-2 by neurons, intracellular signal-transducing protein-6(STATE), Janus kinase 1, Janus kinase 6, CD40, CD86 and/or NF-kB by Bcells, CD154 in T cells, and suppressor of cytokine signalling-3,phosphodiesterase 4, TNF-α, MCP-1, RANTES, CXCL10, CXCL8 (IL-8),prostaglandin E2 receptor, IL-1β, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13,and IL-23, by one or more other cell types such as immune cells asdescribed herein, airway smooth muscle cells, mucosal cells orkeratinocytes. In these treatments, the F1Cs will also increase theactivity or levels of one or more desired response mediators includingsoluble CD23, cathepsin E, epidermal growth factor receptor, IFNγ, IL-2,IL-12 or IL-18. In treating these conditions, Treatment can be combinedwith other suitable therapies, e.g., corticosteroids such as fluticasonepropionate. The F1Cs can also be used to reduce rebound phenomenafollowing withdrawal of corticosteroid therapies, since the F1Cs have ananti-inflammatory effect without having immunosuppressive side effects.Use of the F1Cs to generate any of these biological responses ortreatments can be by daily or intermittent administration of the F1C tothe subject.

In a related embodiment, the F1Cs are used in allergen vaccinationprotocols to enhance levels or activity of allergen specific IgA or IgG,which contributes to reducing IgE responses to allergen exposure. Suchprotocols are used to decrease a subject's sensitivity to allergenexposure. Typically such allergies are chronic or atopic. In theseapplications, the vaccination protocol typically uses the allergen(s) oran active fragment(s) of the allergen that is associated with theallergy or atopic condition. In these methods, a F1C is administered toa subject who has an IgE mediated allergy or atopy condition inconjunction with administration of the allergen. Allergens typicallyused include dermatophagoides, house dust, cat allergen and pollen. Inany of these methods isotype switching or vaccination methods, the F1Cis typically administered as described herein, e.g., by administeringthe F1C about 1, 2, 3, 4, 5, 6, 7, 8, or more days before the allergenis administered to the subject. The subject may receive about 1-20 mg/kgof a F1C at 2, 3 and 4 days before the allergen is administered orinjected. The F1C treatment increases allergen specific IgA or IgGresponses or levels relative to untreated controls. The use of F1C withallergens will reduce the total number of anti-allergic vaccinationsthat are needed, increase the quality or length of an effective responseand/or increase the proportion of subjects in which allergy shots areeffective. An effective response is seen in about 55%, 60%, 65%, 70%,75%, 80% or more of vaccinated patients who also receive the F1Ccompared to about 40-50% of vaccinated patients who do not receive theF1C.

In treating inflammation or any condition described herein whereinflammation contributes to the condition, the F1Cs may detectablymodulate, e.g., decrease or increase, the expression or level oractivity of one or more biomolecules associated with the prevention,establishment, maintenance or progression of the inflammation condition.Such biomolecules include one or more of carcinoembryonic antigen,prostate specific antigen, her2/neu, Bcl-XL, bcl-2, p53, IL-1α, IL-1β,IL-6, or TNFα, GATA-3, COX-2, NFκB, IkB, an IkB kinase, e.g., IkBkinase-α, IkB kinase-β or IkB kinase-γ, NFAT, a ras protein such asH-ras or K-ras, cyclin D, cyclin E xanthine oxidase, or their isoforms,orthologs, homologs or mutant forms, which may have either reduced orenhanced biological activity(ies), and which may be detectablydecreased. Biomolecules that can be detectably increased include IL-2,IFNγ, IL-12, T-bet, O6-methylguanine-DNA-methyltransferase, calcineurin,calmodulin, a superoxide dismutase (e.g., Mn, Zn or Cu), a tumorsuppressor protein such as the retinoblastoma protein (Rb) or CDKN2A(p16), BRCA1, BRCA2, MeCP2, MBD2, PTEN, NBR1, NBR2 or the isoforms,orthologs, homologs or mutant forms, which may have either attenuated orenhanced biological activity(ies), of any of these molecules. One ormore of these biomolecules may be modulated in any inflammationcondition described herein.

The use of any F1C or species in any genus of F1Cs disclosed herein totreat, prevent or ameliorate any of these autoimmune, inflammatory orallergy conditions or symptoms will generally use one or more of theroutes of administration, dosages and dosing protocols as disclosedherein. Thus, in exemplary embodiments, about 0.5 to about 100 mg/kg orabout 1 mg/kg to about 15 mg/kg, of the F1C will be administered per dayby, e.g., an oral, buccal, sublingual, topical or parenteral route. Suchadministration can be, e.g., daily for about 5 to about 60 days in acuteconditions or it can be intermittent for about 3 months to about 2 yearsor more for chronic conditions. Alternatively, intermittent dosing canbe used essentially as described herein for acute autoimmune,inflammatory and allergy conditions.

In another aspect of the invention, the F1Cs can be used to treat or toreduce the severity of chronic allergies or atopic diseases such asallergic rhinitis, psoriasis, eczema, gastrointestinal allergies, atopicdermatitis conditions, allergic asthma, food allergies and hay fever.These conditions are typically characterized by the presence of elevatedlevels of the IgE isotype and of B cells that generate IgE. In treatingor ameliorating these conditions, the F1Cs reduce the generation of IgEby facilitating an isotype switch from B cells that produce IgE to cellsthat produce antigen-specific IgA and/or IgG4. The IgA and IgG4 areallergen specific, which will facilitate clearance of allergen frommucosa or other tissue and reduction of chronic or late phase allergicresponses. The F1c can thus be used to increase the biological clearanceof allergens from tissue. Reduced generation of the levels or activityof IgE by B cells in response to treatment with a F1C and relatedresponses is facilitated at least in part by decreased production of oneor more biological response mediators, e.g., cytokines or responsemediators such as protein kinase A inhibitors, substance P neuropeptide,thymus- and activation-regulated chemokine, e.g., by airway smoothmuscle cells, proteinase activated receptor-2 by neurons, intracellularsignal-transducing protein-6 (STATE), Janus kinase 1, Janus kinase 6,CD40, CD86 and/or NF-κB by B cells, CD154 in T cells, and suppressor ofcytokine signalling-3, phosphodiesterase 4, TNF-α, MCP-1, RANTES,CXCL10, CXCL8 (IL-8), prostaglandin E₂ receptor, IL-1β, IL-4, IL-5,IL-6, IL-10, IL-13 and IL-18 by one or more other cell types such asimmune cells as described herein, airway smooth muscle cells, mucosalcells or keratinocytes. In these treatments, the F1Cs will also increasethe activity or levels of one or more desired response mediatorsincluding cathepsin E, epidermal growth factor receptor, IFNγ, IL-2,IL-12. In treating these conditions, Treatment can be combined withother suitable therapies, e.g., corticosteroids such as fluticasonepropionate. The F1Cs can also be used to reduce rebound phenomenafollowing withdrawal of corticosteroid therapies, since the F1Cs have ananti-inflammatory effect without having immunosuppressive side-effects.Use of the F1Cs to effect any of these biological responses ortreatments can be by daily or intermittent administration of the F1C tothe subject.

In a related embodiment, the F1Cs are used to enhance isotype switchingfrom IgE to IgG in these chronic allergies or atopic diseases invaccination protocols that use the allergen(s) or an active fragment(s)of the allergen that is associated with the allergy or atopic condition.In these methods, a F1C is administered to a subject who has an elevatedIgE allergy or atopy condition in conjunction with administration of theallergen. The subject's response to the allergen is an enhancedproportion of B cells that produce IgG compared to B cells that generateIgE. Allergens typically used include dermatophagoides, house dust, catallergen and pollen. In these methods, the F1C is typically administeredabout 1, 2, 3, 4, 5, 6, 7, 8, or more days before the allergen isadministered to the subject, e.g., the subject receives about 1-20 mg/kgof a F1C at 2, 3 and 4 days before the allergen is administered orinjected. The F1C facilitates isotype switching to IgG. The use of F1Cwith allergens will reduce the total number of anti-allergicvaccinations that are needed, increase the quality or length of aneffective response and/or increase the proportion of subjects in whichallergy shots are effective, e.g., an effective response is seen inabout 55%, 60%, 65%, 70%, 75%, 80% or more of vaccinated patients whoalso receive the F1C compared to about 40-50% of vaccinated patients whodo not receive the F1C.

The F1Cs are suitable for enhancing immune responses in aging insubjects such as humans or primates. In humans at about 50 to 60 yearsof age and later, one or more aspects of immune responses will typicallydecrease by a detectable amount compared to typical immune responses atyounger ages, e.g., at about 18-50 years of age. The F1Cs can be used onan intermittent basis or continuously in aged subjects. Intermittentadministration of a F1C can occur as described herein, e.g., dailydosing or dosing every other day or every third day for about 1, 2, 3,4, 5, 6, 7, 8 or 9 days, followed by about 2, 3, 4, 5, 6, 7, 8, 9 or 10weeks of no dosing, optionally followed by about 1, 2, 3, 4, 5, 6, 7 or8 days of daily dosing or dosing every other day or every third day andthen followed by about 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of no dosing.Such dosing cycles can be repeated indefinitely or as needed. Suchtreatments can be used prophylactically or therapeutically. Inprophylaxis the F1C are administered, e.g., before or during influenzaoutbreaks, or in aged patients in hospitals or in aged patients in longterm living or care facilities such as retirement communities or nursinghomes. In therapeutic applications, the F1C are used to treat trauma,e.g., bone fractures or active infections. The F1C treatments in theseembodiments will result in enhanced immune responses, includingincreased innate and specific responses to, e.g., infectious agents.These treatments will typically also have other beneficial effectsincluding enhancing bone marow production of blood cells or bloodcomponents such as neutrophils or improving levels of dysregulatedimmune response mediators, e.g., decreasing elevated cortisol, IL-6,IL-10, COX-2 or C reactive protein levels or increasing low IL-2 orIL-12 levels.

In related embodiments, the use of the F1C is optionally combined withone or more additional known or experimental therapies for anautoimmune, inflammatory or allergy disorder(s), e.g., one or more ofsurgery and treatment with a corticosteroid or glucocorticoid such ashydrocortisone, hydrocortisone acetate, fludrocortisone, prednisone,prednisolone, prednisolone acetate, methylprednisolone, dexamethasone,dexamethasone acetate or triamcinolone acetonide, leflunomide, anantibody, e.g., a human or humanized monoclonal antibody, that decreasesthe activity or level of C5 complement, TNFα or TNFα receptor, anantirheumatic drug such as methorexate, D-penicillamine, sodiumaurothiomalate, sulfasalazine or hydroxychloroquine, immunosuppressiveagents such as 6-thioguanylic acid, chlorambucil, cyclophosphamide orcyclosporin, a non-steroidal antiinflammatory agent such as celecoxib,ibuprofin, piroxicam or naproxin, an antihistamine such as loratidine orpromethazine hydrochloride, an analgesic such as propoxyphene napsylate,acetaminophen or codeine or administration of vitamins (e.g.,multivitamins, individual vitamins), antioxidants or other agents (e.g.,vitamin E, folinic acid, carnitine, a C2-8 alkanoyl carnitine such asacetyl or propionyl L-carnitine) or nutritional supplements (e.g.,liquid protein or carbohydrate preparations). Such therapies would beused essentially according to standard protocols and such they wouldprecede, be concurrent with or follow treatment with a F1C. In someembodiments, such additional therapies will be administered at the sametime that a F1C is being used or within about 1 day to about 16 weeksbefore or after at least one round of treatment with the F1C iscompleted. Other exemplary therapeutic agents and their use have beendescribed in detail, see, e.g., Physicians Desk Reference 54^(th)edition, 2000, pages 303-3267, ISBN 1-56363-330-2, Medical EconomicsCo., Inc., Montvale, N.J. One or more of these exemplary agents can beused in combination with a F1C to ameliorate, prevent or treat any ofthe appropriate autoimmune, inflammatory or allergy conditions ordisorders described herein or any of their symptoms.

Where a natural or synthetic antiinflammatory glucocorticoid is used totreat one more of the conditions disclosed herein or wherein endogenouslevels of glucocorticoid such as cortisol are elevated to an unwantedlevel in a subject, the use of a F1C will ameliorate unwantedside-effects of such glucocorticoid use or excess. Typically the F1Cwill be administered during, before and/or after glucocorticoid levelsare elevated or during, before and/or after a therapeutic glucocorticoidis administered to the subject, e.g., within about 1, 2, 3, 4, 5, 6 or 7days or within about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 20 or24 weeks before or after glucocorticoid use or elevated glucocorticoidlevels exist. Typically, the use of the F1C to counteract unwantedside-effects of therapeutic glucocorticoid use In these embodiments,will reduce or ameliorate the onset, severity or progression of one ormore unwanted side-effects of glucocorticoid therapy such as adetectable immune suppression, an increased occurrence or incidence ofinfection, an undesirable alteration of mood (e.g., increased anxiety,depression or schizophrenia) or a detectable loss or alteration ofmemory.

Neurological conditions. Nervous system diseases, disorders, conditions,or their symptoms (collectively ‘neurological conditions’) that can beameliorated, treated or prevented with any of the F1Cs disclosed hereininclude, but are not limited to, nervous system trauma or injury, andneurological conditions that result in an unwanted pathology or symptom,e.g., demyelination, pain, impairment of cognitive function, discernablememory loss, depression, anxiety, a disconnection of axons, a diminutionof neuron, astrocyte or glia function or degeneration or death ofnervous system cells or tissues such as one or more of those describedherein.

Neurological conditions, including nervous system lesions that may betreated, prevented, or ameliorated in a subject include but are notlimited to, the following lesions of either the central (includingspinal cord, brain) or peripheral nervous systems. Exemplaryneurological conditions include (1) ischemic lesions, in which a lack ofoxygen in a portion of the nervous system results in neuronal injury ordeath, including cerebral infarction, ischemia or stroke, or spinal cordinfarction or ischemia, (2) traumatic lesions, including lesions causedby physical injury or associated with surgery, for example, lesionswhich sever a portion of the nervous system, or compression injuries,(3) malignant lesions, in which a portion of the nervous system isdestroyed or injured by malignant tissue which is either a nervoussystem associated malignancy or a malignancy derived from non-nervoussystem tissue, (4) infectious lesions, in which a portion of the nervoussystem is destroyed or injured as a result of infection, for example, byan abscess or associated with infection by human immunodeficiency virus,herpes zoster, or herpes simplex virus or with Lyme disease,tuberculosis or syphilis, (5) degenerative lesions or conditions, inwhich a portion of the nervous system is destroyed or injured as aresult of a degenerative process including but not limited todegeneration associated with Parkinson's disease, Alzheimer's disease,Huntington's chorea, AIDS associated dementia, eplieptic dementia,presenile dementia, senile dementia, vascular dementia, post strokedementia, post traumatic dementia or amyotrophic lateral sclerosis(ALS), (6) lesions associated with nutritional diseases, disorders,and/or conditions, in which a portion of the nervous system is destroyedor injured by a nutritional disorder or disorder of metabolism includingbut not limited to, vitamin B 12 deficiency, folic acid deficiency,Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease(primary degeneration of the corpus callosum), and alcoholic cerebellardegeneration, (7) neurological lesions associated with systemic diseasesincluding, but not limited to, diabetes (diabetic neuropathy, Bell'spalsy), systemic lupus erythematosus, carcinoma, or sarcoidosis, (8)lesions caused by toxic substances including alcohol, lead, orneurotoxins, (9) demyelinated lesions in which a portion of the nervoussystem is destroyed or injured by a demyelinating disease including, butnot limited to, multiple sclerosis, human immunodeficiencyvirus-associated myelopathy, progressive multifocal leukoencephalopathy,and central pontine myelinolysis or a myelopathy, e.g., diabeticmeylopathy or a transverse myelopathy, (10) neurological conditions suchas insomnia (e.g., transient or chronic), epilepsy, schizophrenia,psychosis, delusion, a unipolar mood disorder, a bipolar mood disorder,psychomotor dysfunction, depression, anxiety, addiction to or abuse of adrug substance such as tobacco, nicotine, caffeine, alcohol, abarbiturate, a tranquilizer, a narcotic such as hydromorphone HCl,propoxyphene napsylate, meperidine HCl, valium, codeine, cocaine,morphine, heroin or methadone, (11) cognitive dysfunction conditions ordiseases such as one or more of impaired long-term or short-term memory,impaired concentration, impaired attention or impaired learning, wherethe cognitive dysfunction condition or disease is optionally associatedwith chemotherapy, radiation therapy or exposure, aging, trauma, e.g.,CNS trauma, or neurodegeneration and (12) genetic disorders with aneurological pathology or component such as Down's syndrome or TaySach's disease.

The F1Cs are useful to ameliorate, treat or prevent the onset, severityor length of other neurological diseases or conditions such as headacheor a migraine condition or symptom such as classic migraine, clusterheadache, abdominal migraine, common migraine, hemiplegic migraine,ocular migraine, fulminating migraine, complicated migraine or a symptomof any of these such as head pain, vertigo, nausea, vomiting orpotophobia.

In some embodiments, the F1C is used to protect neural cells from thedamaging effects of cerebral hypoxia, cerebral ischemia or neural cellinjury associated with cerebral infarction, heart attack, stroke orelevated levels of glucocorticoids such as cortisol. The compounds thatare also useful for treating or preventing a nervous system disorder maybe selected, e.g., by assaying their biological activity in promotingthe survival or differentiation of neurons. For example, and not by wayof limitation, the F1Cs can be used to elicit any of the followinguseful effects: (1) increased survival time of neurons in culture, (2)increased sprouting of neurons in culture or in vivo, (3) increasedproduction of a neuron-associated molecule in culture or in vivo, e.g.,dopamine or choline acetyltransferase or acetylcholinesterase withrespect to motor neurons or (4) decreased symptoms of neuron dysfunctionin vivo. Such effects may be measured by any method known in the art.Increased survival of neurons may be measured using known methods, suchas, for example, the method set forth in Arakawa et al. (J. Neurosci.10:3507-3515 1990); increased sprouting of neurons may be detected bymethods known in the art, such as the methods set forth in Pestronk etal. (Exp. Neurol. 70:65-82 1980) or Brown et al. (Ann. Rev. Neurosci.4:17-42 1981). Increased production of neuron-associated molecules maybe measured by, e.g., bioassay, enzymatic assay, antibody binding orNorthern blot assay, using techniques known in the art and depending onthe molecule to be measured. Motor neuron dysfunction may be measured byassessing the physical manifestation of motor neuron disorder, e.g.,weakness, motor neuron conduction velocity, or functional disability.Motor neuron conditions may arise from infarction, cancer, infection,exposure to toxin, trauma, surgical damage or a degenerative diseasethat affects motor neurons as well as other components of the nervoussystem.

Other neurological conditions that can be treated using F1Cs includeconditions that selectively affect neurons or adjacent tissues such asamyotrophic lateral sclerosis, progressive spinal muscular atrophy,progressive bulbar palsy, primary lateral sclerosis, infantile andjuvenile muscular atrophy, poliomyelitis and the post polio syndrome,hereditary motorsensory neuropathy, spinal cord compression and amyelitis such as necrotizing myelitis, transverse myelitis, ascendingmyelitis, bulbar myelitis, concussion myelitis, demyelinated myelitis,postinfectious myelitis, systemic myelitis or transverse myelitis.

In some neurological conditions such as mood changes, depression,anxiety, memory loss or motor function impairment, the F1Cs can modulateone or more biological activities of a transcription factor or a nuclearhormone receptor such as ERα in tissue such as the hypothalamus oramygdala or ERR in tissue such as the hippocampus, thalamus orentorhinal cortex.

In neurological conditions or other conditions where loss or damage tonervous system cells or tissue is typically present, e.g., multiplesclerosis, cerebral infarction, cerebral trauma, elevated glucocorticoidlevels or Alzheimer's disease, use of the F1Cs can lead to detectablerepair of damaged cells or replacement of at least some killed cells.Elevated glucocorticoids can result from endogenous production ofnatural glucocorticoids, e.g., cortisol or hydrocortisone, or fromadministration of synthetic glucocorticoids, e.g., dexamethasone,triamcinolone, betamethasone or other synthetic agents disclosed hereinor in the cited references. Repair or replacement can occur for celltypes that are present in nervous system tissues, e.g., neurons, Schwanncells, glial cells, astrocytes, oligodendrocytes, macroglia cells,endothelial cells, or stem or progenitor cells of any of these celltypes. The cells may reside in discrete regions of nervous organs, e.g.,hippocampus, cerebrum or cerebellum, or they may reside in multipleregions. Any of the neurological conditions that can be treated with theF1Cs may be acute, subacute or chronic and they may be subclinical(having few or no overt symptoms), mild, moderate or severe.

In treating neurological conditions, the F1Cs will generally enhancefunction, self renewal and/or differentiation of stem or progenitorcells and/or they will reduce the severity of cell damage or impairmentcompared to similar subjects that are not treated with the F1Cs. Incases where myelin damage or nerve death occurs, the F1Cs can reduce therate at which damage or death occurs or they can detectably reversedamage or enhance replacement of killed cells, particularly where theextent of such damage or killing is mild or moderate. Without wishing tobe bound to any theory, the F1Cs may exert these properties (1) bydirectly acting as a hormone, growth factor or modulator of abiomolecule disclosed herein such as an enzyme, a glucocorticoidreceptor, PPARα, a neural stem cell helix-loop-helix transcriptionfactor such as HES1 or an estrogen receptor to enhance replication,synaptogenesis or other repair or maintenance functions, (2) byenhancing recruitment and/or differentiation of cells involved in cellor tissue repair, e.g., enhanced recruitment and differentiation ofoligodendrocyte cells to a demyelinated lesion in multiple sclerosisand/or (3) indirectly by modulating the level or activity of autocrine,paracrine or endocrine factors such as one or more inflammatorycytokines or markers as disclosed herein that can modulate diseaseprogression, e.g., cortisol, IL-1α, IL-1β, TNF-α, IL-6, a thromboxane, aprostaglandin or a neuregulin.

In treating chronic or progressive disorders such as multiple sclerosisor Alzheimer's disease, the F1Cs will typically slow the rate ofprogression of the disease. The F1Cs act at least in part by decreasingthe activity or levels of chemokines and/or pro-inflammatory cytokines,e.g., one, two or more of MCP-1, MIP-1, ICAM, V-CAM, E-selectin, RANTES,IL-1α, IL-1β, IL-6, IL-8 and TNF-α. This reduction can be accompanied bya reduced rate of deposition of amyloid-β (AJ3) protein, which resultsin slowed disease progression and in reduced severity and/or frequencyof one or more symptoms such as short term memory loss, impairedconcentration, impaired judgement, episodes of disorientation orconfusion and periods of mood or behavior changes such as irritability,anxiety or aggression. Treatment of chronic or progressive disorderssuch as Alzheimer's disease with a F1C is optionally accompanied byother suitable treatments, e.g., treatment with one or morenon-steroidal anti-inflammatory drugs or other palliative measures.

Factors such as increased levels of cortisol or thromboxane, that areassociated with increased cell or tissue damage or with inhibition ofcell growth or differentiation are generally decreased or reregulated toexpress in a normal manner by the appropriate cells such as neurons,astrocytes, glial cells or their stem or precursor cells. Factors thatfacilitate normal differentiation or repair, e.g., basic fibroblastgrowth factor 2 or neuregulin, are generally increased or reregulated toexpress in a normal manner by the appropriate cells such as neurons,astrocytes, glial cells or their stem or precursor cells.

Because of these properties, the F1Cs can be used in various protocolsor methods to enhance differentiation or proliferation of these celltypes in vivo or in vitro. Typically, the concentration of the F1Cs willexert one or more of these beneficial effects at extracellularconcentrations of about 1×10⁻¹² M to about 5×10⁻⁶ M, e.g., about 1×10⁻¹¹M to about 5×10⁻⁷ M or about 1×10⁻¹⁰ M to about 1×10⁻⁷ M. Suchconcentrations can suitably be established transiently, e.g., for about10 minutes to about 6 hours or about 12 hours once or twice per day onone, two or more days. Alternatively, such concentrations may bemaintained more or less constantly, e.g., within these ranges for atleast about 12 hours per day for one, two or more days, particularly forin vitro use to enhance cell or tissue growth, differentiation orviability in tissue culture. Methods to administer the F1Cs for in vivouse are essentially as described herein.

For any of these neurological conditions or their associated symptoms,the presence of the condition or its pathological manifestation, e.g.,cell or tissue damage, or symptom may be determined by suitableobjective or subjective means, e.g., assays to detect tissue damage,levels of diagnostic markers or an etiological agent, performance ofhistopathological examination of cells or tissues, patientquestionnaires or behavior performance tests, measurement of adiagnostic marker(s), e.g., an enzyme, hormone, cytokine or drugsubstance in blood or tissue, electroencephalography, imaging methodssuch as X-ray, MRI scan or CAT scan, observation and diagnosis ofclinical features or symptoms or biopsy of affected tissue or cells,e.g., aspiration biopsy, needle biopsy, incision biopsy or punch biopsyof tissue or cells. Neurological conditions, diseases and symptoms,which the F1Cs can be used to treat or ameliorate and methods todiagnose and characterize such conditions or diseases have beendescribed. See, e.g., Ph. Demaerel, A. L. Baert et al., eds. RecentAdvances in Diagnostic Neuroradiology (Medical Radiology: DiagnosticImaging) 2001 Springer Verlag, ISBN: 3504657231, W. G. Bradley et al.,Neurology in Clinical Practice: Principles of Diagnosis and Management1995, see, e.g., vol. 1 Ch. 1-55 and vol. 2. Ch. 1-66,Butterworth-Heinemann Medical, ISBN 0750694777, H. J. M. Barnett et al.,eds. Stroke: Pathophysiology, Diagnosis and Management 3^(rd) edition,1998, see, e.g., pages 10-1450, Churchill Livingstone, ISBN 0443075514,P. J. Vinken et al., eds. Neurodystrophies and Neurolipidoses 2^(nd) ed.1996, see, e.g., pages 8-780, Elsevier Science, ISBN 0444812857, P. L.Peterson and J. W. Phillis eds. Novel Therapies for CNS Injuries:Rationales and Results 1995, see, e.g., pages 8-380, CRC Press, ISBN0849376521, D. Schiffer, Brain Tumors: Pathology and Its BiologicalCorrelates 2^(nd) ed. 1997, see, e.g., pages 5-450, Springer Verlag,ISBN 3540616225 and E. Niedermeyer and F. Lopes Da Silva, eds.Electroencephalography: Basic Principles, Clinical Applications andRelated Fields 4^(th) ed. 1999 see, e.g., pages 13-1238, Lippincott,Williams & Wilkins, ISBN 0683302841.

The use of the F1Cs in these conditions is optionally combined with oneor more of the therapeutic treatments that are described in thesereferences. The F1C may be administered before, during or after anothertreatment is employed to prevent, treat or ameliorate a givenneurological condition or symptom thereof. Any of these neurologicalconditions or symptoms may be mild or at an early stage, moderate orsevere or advanced.

Dosages of the F1C, routes of administration and the use of combinationtherapies with other standard therapeutic agents or treatments could beapplied essentially as described above for cardiovascular conditions oras disclosed elsewhere herein. Thus, the F1Cs may be administeredprophylactically or therapeutically in chronic conditions or they may beadministered at the time of or relatively soon before or after an acuteevent such as an epileptic seizure, onset of a migraine or occurrence oftrauma, before, during or after surgery, accidental head or centralnervous system injury or a cerebral stroke or infarction. For acuteevents, the formula 1 compounds may thus be administered concurrently,e.g., within about 15 minutes or about 30 minutes of the onset oroccurrence of the acute event, or at a later time, e.g., at about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 26, 28,30, 36, 42, 48, 54, 60, 72, 84, 96, 108 or 120 hours after the onset oroccurrence of the acute event. The F1Cs may thus be administered atabout 6-120 hours, or about 8-48 hours, about 10-24 hours or about 12-16hours after an acute event starts or occurs. In other embodiments, theF1C can be administered before an expected acute event such as a plannedsurgery. In these cases, the F1Cs may be administered before, e.g.,within about 15 minutes or about 30 minutes of the onset or occurrenceof the acute event, or at an earlier time, e.g., at about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 26, 28, 30, 36,42, 48, 54, 60, 72, 84, 96, 108 or 120 hours before the onset oroccurrence of the acute event.

Skin treatments. The affect of the F1Cs on immune function permits theiruse to improve the function of organs or organ systems that rely on theoptimal functioning of one or more immune responses. Thus, the F1Cs canbe administered to a subject to prevent, treat, ameliorate, slow theprogression of or enhance the healing of certain skin conditions such asskin inflammation, lesions, atrophy or rash. Conditions that can giverise to skin pathology or an unwanted skin condition include autoimmunediseases, inflammation, allergy, age, exposure to sunlight, cancer,infection or the like.

As used here, skin includes external skin and internal skin or surfacessuch as oral, intestinal and rectal mucosa. These conditions includelesions, rashes or inflammation associated with, e.g., burns, infectionsand the thinning or general degradation of the dermis oftencharacterized by a decrease in collagen or elastin as well as decreasednumber, size and doubling potential of fibroblast cells. Such skinconditions include keratoses such as actinic keratosis, psoriasis,eczema, warts such as papillomavirus-induced warts, ulcers or lesionssuch as herpesvirus-induced ulcers or lesions or diabetes associatedulcers or lesions, discoid lupus erythematosus, erythema nodosum,erythema multiform, cutaneous T cell lymphoma, atopic dermatitis,inflammatory vasculitis, relapsing polychondritis, exfoliativedermatitis, sarcoidosis, burns, melanoma, rash or irritation from poisonoak, poison ivy or poison Sumac, blemished or hyperpigmented skin,hyperkeratotic skin, dry skin, dandruff, acne, inflammatory dermatoses,scarring such as from a chemical or thermal burn and age-related skinchanges. In these embodiments, treatment with the F1Cs is optionallycombined with other appropriate treatments or therapies essentially asdescribed herein, e.g., one or more of a corticosteroid such ashydrocortisone or cortisol, prednisone, or prednisolone, anα-hydroxybenzoic acid or an α-hydroxycarboxylic acid(s) iscoadministered with a F1C to treat, prevent or ameliorate a skincondition such as atrophy or a lesion. α-Hydroxybenzoic acids andα-hydroxycarboxylic acids suitable for use in these embodiments aredescribed in, e.g., U.S. Pat. Nos. 5,262,407, 5,254,343, 4,246,261,4,234,599 and 3,984,566. The F1C can be used to minimize cutaneousatrophy caused by corticosteroids, a side effect of their application tothe skin.

In these embodiments that address skin conditions, dosages, routes ofadministration and dosing protocols for the F1Cs are essentially asdescribed herein. In some embodiments, the F1C is administered to thesubject in the form of a topical cream, ointment, spray, foam or gel.These topical formulations will optionally comprise about 0.1% w/w toabout 20% w/w, or about 0.2% w/w to about 10% w/w of a F1C in acomposition that comprises one or more excipients that are suitable forsuch topical formulations, including, e.g., one or more agents thatenhance penetration or delivery of the F1C into the skin. Such topicalformulations can be administered, e.g., once, twice or three times perday using about 0.1 g to about 8 g or about 0.2 g to about 5 g of thetopical formulation on each occasion. Administration may be daily forabout 1 to about 28 days, or it may be intermittent and used as needed.The amount of a topical formulation that can be administered may behigher, e.g., about 15 g or about 20 g, if the size of the area to betreated is relatively large, e.g., at least about 30 cm² to about 100cm² or more. Alternatively, systemic administration of the F1C such asoral, parenteral, sublingual or buccal delivery may be used,particularly when the area of the skin to be treated is relativelylarge. In some cases, both topical and systemic administration of a F1Ccan be used. Excipients that topical or other formulations may containinclude those described herein, or agents that enhance permeation orsolubilization of the F1C, e.g., DMSO or an alkylalkanol, such as a2-alkylalkanol or a 3-alkyloctanol that comprises about 8-36 carbonatoms (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbonatoms) such as 2-ethyloctanol, 2-propyloctanol, 2-octyldodecanol,2-butyloctanol, 2-hexyldecanol, 2-pentylnonanol, 3-ethyloctanol,3-propyloctanol, 3-octyldodecanol, 3-butyloctanol, 3-hexyldecanol,3-pentylnonanol, isostearyl alcohol, isocetyl alcohol, or mixturesthereof. Such alkylalkanol moieties include those having the structureHO—CH₂—(CH₂)₀₋₄—CH(C1-10 alkyl)-(CH₂)₀₋₆—CH₃, any of which areoptionally substituted at the alkanol or the alkyl moiety with one, two,three or more independently selected substituents as described herein,e.g., with one, two, three or more independently selected —O—, —F, —OH,—CN or —CH═CH— moieties. Such formulations can be used in therapeuticapplications described herein or in cosmetic applications.

Modulation of transcription factors, receptors and gene expression. Intreating any of the diseases, conditions or symptoms disclosed herein,the F1Cs can modulate, i.e., detectably enhance or increase ordetectably inhibit or decrease, the expression or a biologicalactivity(ies) of one or more transcription factors or receptors. Thiscan lead to detectable modulation of target gene activity or expressionas part of the treatment or amelioration of the disease, condition orsymptom. Such modulation can arise from changes in the capacity of atranscription factor or receptor to bind to or form a complex with othernatural ligands such as a target DNA sequence(s), another transcriptionfactor(s), a transcription cofactor, a receptor such as a nuclearhormone receptor or cell membrane receptor (e.g., a lipid, peptide,protein or glycoprotein receptor such as an interleukin receptor or agrowth factor receptor), a receptor cofactor or an enzyme such as apolymerase, kinase, phosphatase or transferase. The effects of F1Cs onthese biomolecules can be exerted in immune cells or in non-immunetissue, e.g., cells or tissue adjacent to diseased tissue such asinfected or malignant cells. The F1Cs may directly or indirectlymodulate the capacity of any of these molecules to transduce signalsthat are part of normal signal trandsuction processes.

In many of the clinical conditions described herein, e.g., in cancers,infections, acute inflammation, chronic inflammation, trauma,neurological conditions or autoimmunity, the F1Cs can modulate, e.g.,detectably decrease or increase, a biological activity(ies), protein ormolecule level or RNA level of 1, 2, 3, 4, 5, 6 or more biomoleculesthat are involved in establishment, maintenance or progression of adisease, condition or symptom. Such biomolecules include 1, 2, 3, 4, 5,6 or more of AP-1, a cyclooxygenase such as mammalian or humancyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2), a mammalian orhuman lipoxygenase, e.g., 5-lipoxygenase, TNFα, TNFα receptor 1, TNFαreceptor 2, TNF receptor-associated factor, TNFβ, TNFβ receptor, MIP-1α,monocyte chemoattractant-1 (MCP-1), interferon gamma (IFNγ or γIFN),IL-1α, IL-1β, IL-1α receptor, IL-1β receptor, IL-2, IL-3, IL-4, IL-4receptor (IL-4R), IL-5, IL-6, IL-6 receptor (IL-6R), IL-8, IL-8 receptor(IL-8R), IL-10, IL-10 receptor (IL-10R), IL-12, an IL-12 receptor,(e.g., IL-12Rβ2), IL-13, IL-15, IL-17, IL-18, nuclear factor kappa B(NFκB), AP-1, c-maf, v-maf, mafB, NrI, mafK, mafG, the maf familyprotein p18, reactive oxygen species, e.g., peroxynitrite, hydrogenperoxide or superoxide ion (collectively ROS), a 17β-hydroxysteroiddehydrogenase (17β-HSD) or an 11β-hydroxysteroid dehydrogenase(11β-HSD), e.g., 11β-HSD type 1, 11β-HSD type 2, 17β-HSD type 1, 17β-HSDtype 2 or 17β-HSD type 5, a steroid aromatase, e.g., cytochrome P450aromatase, steroid 5α-reductase, serum or blood cortisol, cytosolicphospholipase A2 (cPLA2), calcium-independent phospholipase A2 (iPLA2),a prostaglandin, e.g., prostaglandin E2 (PGE2) or prostaglandin D2(PGD2), a leukotriene, e.g., leukotriene B4, inducible nitric oxidesynthetase (iNOS), nitric oxide (NO), GM-CSF, RANTES (regulated onactivation, normal T cells expressed and secreted), eotaxin, GATA-3,CCR1, CCR3, CCR4, CCR5, CXCR4, in, e.g., a subject's cell(s) ortissue(s) or in enzyme, tissue or cell-based assays. In these subjects,the levels of other biomolecules, their RNAs or the level of theiractivity can be detectably modulated include IFNα, INFα receptor, PPARα,PPARγ, PPARδ or a transcription factor such as T-bet is detectablyincreased. Other biomolecules or their isoforms, polymorphs, orthologs,or homologs that the F1Cs directly or indirectly modulate include one ormore of, e.g., Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Januskinase 3 (JAK3), signal transducer and activator of transcription 1(STAT1), signal transducer and activator of transcription 2 (STAT2) andsignal transducer and activator of transcription 3 (STAT3). The F1Cs canmodulate the other biologically active analogs of any these enzymes,chemokines, cytokines, their receptors or ligands, including theirisoforms, polymorphs, orthologs or homologs. In some cells or tissues,one or more of these biomolecules may be detectably increased, while inother cells or tissues, the same biomolecule may be detectablydecreased. Thus, the biomolecules that the F1Cs can modulate, e.g.,detectably increase or decrease, include the intracellular orextracellular level or biological activity of one or more enzyme,cytokine, cytokine receptor, chemokine and/or chemokine receptor.Exemplary chemokine receptors include one, two or more of CCR-1, CCR-2,CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3 and CXCR-4.

The F1Cs can modulate the activity of certain biomolecules that mediatevarious biological responses that affect establishment or progression ofa disease or that enhance or inhibit specific immune responses. Thus, inconditions where unwanted inflammation is present, the F1Cs can reduceinflammation, while enhancing Th1 or Tc1 immune responses at the sametime. The biomolecules that the F1Cs can modulate include, e.g.,transcription factors or receptors, including orphan nuclear receptors,and the homologs, isoforms, orthologs and co-factors (e.g.,co-repressors, co-activators, transcription factors, gene promoterregions, sequences or messenger moieties such as calcium ions, potassiumions or cAMP) of any of these molecules and related molecules thatparticipate in their function. The compounds can directly or indirectlyfrom complexes with such molecules or they can modulate (detectablyincrease or decrease) the synthesis, level or one or more biologicalactivities of those molecules. These complexes include receptors ortranscription factor complexes, which can comprise heterodimers,homodimers and trimer, tetramer, pentamer or higher homo or heterocomplexes. A number of the orphan receptors or their isoforms, orthologsor homologs, e.g., PPARα, PPARβ, PPARγ, PPARγ1, PPARγ2, PPARγ3, LXRα,LXRβ, SXR, PXR, CARα and CARβ, can form heterodimers with one or more ofRXRα, RXRβ and RXRγ. Exemplary mammalian, human or other biomoleculesinclude steroidogenic factor-1 (SF-1), steroidogenic acute regulatoryprotein (StAR), a chicken ovalbumin upstream promoter-transcriptionfactor (COUP-TF), chicken ovalbumin upstream promoter-transcriptionfactor (COUP-TFI) and its mammalian isoforms, orthologs and homologs,silencing mediator for retinoid and thyroid hormone receptor (SMRT) andits mammalian isoforms, orthologs and homologs, sterol regulatoryelement binding protein (SREBP) 1a (SREBP-1a), SREBP-1c, SREPB-2, NF-E3,FKHR-L1, COUP-TFII and its mammalian isoforms, orthologs and homologs,and the isoforms, orthologs and homologs of IκB, IκBα, AML-3, PEBP2αA1,Osf2, Cbfa1, RUNX2, activating transcription factor 2 (ATF2), c-Jun,c-Fos, a mitogen activated kinase (MAP) such as p38 or JNK, a mitogenactivated kinase kinase (MKK), a p160 or steroid receptor coactivator-1family (SRC-1, SRC-1/serum response factor), SRC-2, SRC-3, SET, nervegrowth factor inducible protein B, StF-IT, NFAT, NFAT interactingprotein 45 (NIP45), IkB, an IkB kinase, NFATp, NFAT4, an AP-1 familyprotein, a p300 protein, CREB, CREB-binding protein (CPB), p300/CBP,p300/CPB-associated factor, SWI/SNF and their human and other homologs,BRG-1, OCT-1/OAF, AP-1, AF-2, Ets, androgen receptor associated protein54 (ARA54), androgen receptor associated protein 55 (ARA55), androgenreceptor associated protein 70 (ARA70), androgen receptor-interactingprotein 3 (ARIP3), ARIP3/PIASx α complex, PIASx α, Miz1, Miz1/PIASx βcomplex, PIASx β, PIAS1, PIAS3, GBP, GBP/PIAS1 complex, RAC3/ACTRcomplex, SRC-1α, receptor interacting protein-140 (RIP-140),transcription factor activator protein-1, activation function-2,glucocorticoid receptor-interacting protein-1 (GRIP-1), receptorinteracting protein-160 (RIP-160), suppressor of gal4D lesions (SUG-1),transcription intermediary factor-1 (TIF-1), transcription intermediaryfactor-2 (TIF-2), SMRT, N—CoR, N—CoA-1, p/CIP, p65 (RelA), the 120 KDrel-related transcription factor, heat shock proteins (HSP) such asHSP90, HSP70 and HSP72, heat shock factor-1, Vpr encoded by the humanimmunodeficiency virus and its isoforms and homologs thereof, testicularorphan receptor 2 (TR2), testicular orphan receptor 4 (TR4), a thyroidhormone receptor α, thyroid hormone receptor α1 (TRα1), thyroid hormonereceptor α2 (TRα2), thyroid hormone receptor β (TRβ), retinoid Xreceptor α (RXRα), retinoid X receptor β (RXRβ), retinoid X receptor γ(RXRγ), TR α1/RXR α heterodimer, direct repeat-4 thyroid hormoneresponse element (DR4-TRE), an estrogen receptor (ER) such as ERα orERβ, estrogen receptor related receptor α (ERRα or EER1), estrogenreceptor related receptor β (ERRβ or EER2), estrogen receptor relatedreceptor γ (ERRγ or EER3), steroid xenobiotic receptor (SXR), ahepatocyte nuclear factor 4 (HNF-4), hepatocyte nuclear factor 4γ(HNF-4γ), hepatocyte nuclear factor 3 (HNF-3), liver X receptors (LXRs),LXRα, LXRβ, estrogen receptor α (ERα), constitutive androstanereceptor-α (CAR-α), constitutive androstane receptor-β (CAR-β),RXR/CAR-β heterodimer, short heterodimer partner (SHP; NR0B2), SHP/ERαheterodimer, estrogen receptor β, SHP/ERβ heterodimer, testicular orphanreceptor TR4, TR2/TR4 heterodimer, pregnane X receptor (PXR) andisoforms, cytochrome P-450 monooxygenase 3A4, including its genepromoter region and isoforms thereof, HNF-4/cytochrome P-450monooxygenase 3A4 gene promoter region and isoforms complex, HIV-1 longterminal repeat (LTR), HIV-2 LTR, TR2/HIV-1 LTR complex, TR4/HIV-1 LTRcomplex, TR4/HIV-1 LTR complex, TR α1/TR4/HIV-1 LTR complex, TR2isoforms (TR2-5, TR7, TR9, TR11), DAX-1 (NR0B1), DAX-1/steroidogenicacute regulatory protein gene promoter region, RevErb, Rev-erbA α,Rev-erb β, steroid receptor coactivator amplified in breast cancer (AIB1), p300/CREB binding protein-interacting protein (p/CIP), thyroidhormone receptor (TR, T3R), thyroid hormone response elements (T3REs),retinoblastoma protien (Rb), tumor suppressor factor p53, transcriptionfactor E2F, mammalian acute phase response factor (APRF), constitutiveandrostane receptor (CAR), Xenopus xSRC-3 and mammalian (e.g., human)isoforms, orthologs and homologs, TAK1, TAK1/peroxisomeproliferator-activated receptor α (PPARα) complex, PPARα/RXRα complex,peroxisome proliferator-activated receptor β (PPARβ), peroxisomeproliferator-activated receptor γ (PPARγ), peroxisomeproliferator-activated receptor δ (PPARδ), farnesoid X receptor, retinaX receptor, TAK-1/RIP-140 complex, a retinoic acid receptor (RAR),retinoic acid receptor-β (RARβ), retinoic acid receptor-γ (RARγ),TR4/RXRE complex, SF-1/steroid hydroxylase gene promoter region,SF-1/oxytocin, including its gene promoter region, a bile acid receptor(FXR), nuclear receptor corepressor (NcoR), liver receptor homologousprotein-1 (LRH-1; NR5A2), SF-1/ACTH receptor gene promoter region, ratEar-2 and mammalian homologs, human TR3 orphan receptor (TR3), RLD-1,OR-1, androgen receptor, glucocorticoid receptor, estrogen receptor,progesterone receptor, mineralcorticoid receptor, aldosterone receptor,E6-associated protein (E6-AP), OR1, OR1/RXRα complex, TIF-1, CBP/P300complex, TRIP1/SUG-1 complex, RIP-140, steroid receptor coactivator 1(SRC1), SRC1α/P160 complex and TIF-2/GRIP-1 complex, RAR/N—CoR/RIP13complex, RAR/SMRT/TRAC-2 complex and protein X of hepatitis B virus. Thehomologs, orthologs and isoforms of these transcription factors,receptors and other molecules are included among the molecules that theF1Cs can modulate the synthesis or one or more biological activities of.Such factors are biologically active or function in one or more of anumber of cell types such as T cells, B cells, macrophages, dendriticcells, platelets, monocytes, neutrophils, neurons, epithelial cells,endothelial cells, cartilage cells, osteoblasts, osteoclasts,splenocytes, thymocytes and GALT associated cells. Methods to identifythese molecules and their biological activities have been described,e.g., U.S. Pat. Nos. 6,248,781, 6,242,253, 6,180,681, 6,174,676,6,090,561, 6,090,542, 6,074,850, 6,063,583, 6,051,373, 6,024,940,5,989,810, 5,958,671, 5,925,657, 5,958,671, 5,844,082, 5,837,840,5,770,581, 5,756,673, and PCT publication Nos. WO 00/24245, WO 0073453and WO 97/39721.

In one aspect, the compounds are used to treat, prevent or to ameliorateconditions or symptoms that are associated with unwanted or expressionor activity of one or more of these molecules in conditions such as,e.g., acute inflammation, chronic inflammation or their symptoms, acuteallergy, chronic allergy or their symptoms, e.g., allergic rhinitis oracute or chronic asthma, psoriatic arthritis, osteoporosis,osteoarthritis, rheumatoid arthritis, neurological dysfunction or theirsymptoms, e.g., dementias such as Alzheimer's Disease, Parkinson'sDisease, or memory loss conditions, in osteoporosis or in cancer such asbreast cancer. The compounds can prevent NFκB from translocating fromthe cytoplasm into the nucleus and thus can increase the ratio ofcytoplasmic NFκB to nuclear NFκB. The F1Cs may inhibit activation ofNFκB-mediated transcription while NFκB is bound to target DNA sequencesin the nucleus. Alternatively, the F1Cs can activate or enhance theexpression of or one or more activity of a transcription factor such asT-bet in, e.g., a subject's cell(s) or tissue(s) or in enzyme orcell-based assays. In this aspect the compounds are used to treat,prevent or to ameliorate conditions or symptoms that are associated withdeficient expression or activity of T-bet in conditions such as immunedysfunction in an immunosuppression condition, aging, an infection, acancer or precancer as described herein or in the cited references.

The invention provides methods to identify compounds to regulate immuneor other biological responses in a context-sensitive manner. Suchcompounds modulate differential expression in a cell of the level of oran activity of, eg., 4, 5, 6, 7, 8 or more genes or gene products,comprising administering an effective amount of a F1C. The genes or geneproducts are USF1, c-Fos, EGR1, Cul1, RIPK2, IκBα, IκBKb, NF-κB, NF-κB2,NF-κB1 p50, Fn14 (fibroblast growth factor-inducible 14), TWEAK(TNF-like weak inducer of apoptosis), NEMO (NF-κB essential modifier),FCAR, c-Fos/C/EBPβ, RANTES, ICAM1, TSG (TNFAIP6), IL-2 receptor α, GRO2,GRO3, HO1, Jun B, c-Fos/JunB complex, JunB/ATF3 complex, c-Jun,c-Fos/c-Jun complex, ATF-3, MMP1, TSG-6 (TNFAIP3), AP-1, EGR1, TGFβ,ATF-3/c-Jun complex, c-Fos, MMP3, IL-8, STAT5A, STAT5B, CDKN1A, IFNγreceptor 2 (IFNγR2), T-bet, C reactive protein, immunoglobulin E, anAP-1 family protein, GATA-3, Jak2, Tyk2, stat1, stat3, stat4, stat5,MIP-1α, MIP-2, IP-10, MCP-1, TNF-α, TNF-β, LT-β, IFN-α, IFN-β, TGF-β1,NF-κB, IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12 receptor [3], IL-12p35,IL-12p40, IL-23, IL-23 receptor or another gene or gene productdisclosed herein, including in Table 1. The compounds identified by thescreening methods modulate the expression of dysregulated genes andrestore or enhance normal immune responses in conditions where unwanteddysregulation contributes to the establishment or progression apathological condition such as an infection, an autoimmune disorder, acardiovascular condition or a neurological condition.

Thus, in some embodiments, the level or a biological activity of 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more of COX-2, IL-1β, TNFα, TNFαreceptor 1, TNFα receptor 2, TNF receptor-associated factor, MIP-1α,MCP-1, IFNγ, IL-4, IL-4R, IL-6, IL-6R, IL-8, IL-8R, IL-10, IL-10R,IL-12, IL-12R, IL-18, IL-18R NFκB, IkBα, AP-1, GATA-3, 11β-HSD1, cPLA2,iPLA2, cortisol, ROS, PGE2, PGD2, leukotriene A4, leukotriene B4,leukotriene C4, iNOS or GM-CSF are optionally measured and they aregenerally detectably reduced, e.g., RNA or protein levels are reduced byabout 10-95% or about 20-95% or more compared to suitable untreatedcontrols. In these embodiments, the level or a biological activity of 4,5, 6 or more of IFNα, INFα receptor, IL-12, an IL-12 receptor, (e.g.,IL-12Rβ2), PPARα, PPARγ, and T-bet are optionally measured and they aregenerally detectably increased. In a chronic infection condition, e.g.,HIV in humans, autoimmunity, a chronic fungal or parasite infection orin a precancer or cancer condition, e.g., benign prostatic hyperplasia,the progression of the condition may be slowed over a period of 1, 2, 3,4, 5 or more years. In these embodiments, the subject's conditionbecomes more manageable with a reduced incidence or severity of sideeffects, e.g., a detectable halt, slowing, reversal or decreasedincidence of wasting, dementia, CD4 cell count decreases or viral loadincreases, which tend to occur over time in HIV infected humans or ahalt, slowing or reversal of pathogen or precancer or cancer cellreplication.

These effects are typically observed after administration of aneffective amount of a F1C using, e.g., a method or dose essentially asdisclosed herein. The simultaneous reduction of multiple biomoleculesprovides a method to modulate immune responses by modulating multiplepathways that lead to a common condition such as inflammation. Thisprovides a method to treat or ameliorate, e.g., acute or chronicinflammation, a cancer, an infection or a symptom associated therewith,or to slow the progression of or reduce the severity of these conditionsor their symptoms.

Previously described methods can be used to measure the amount, activityor cellular location of various biomolecules such as cytokines ortranscription factors. See, e.g., U.S. Pat. Nos. 6,107,034, 5,925,657,5,658,744, 4,016,043 and 3,850,752, S. Szabo et al., Cell 2000100:655-669, Y. Nakamura et al., J. Allergy Clin. Immunol. 1999 103(2pt. 1):215-222., R. V. Hoch et al., Int. J. Cancer 1999 84:122-128.These methods can be used to measure the effects of the F1Cs ontranscription factors or receptors in cells or tissues that have beenexposed to the compounds.

Without wishing to be bound to any theory, the F1Cs may modulatemultiple biomolecules in a microenvironment sensitive manner or context.The effects of the compounds can provide a decrease in a particularmolecule such as IFNγ and a decrease in inflammation associated withelevated IFNγ levels or activity without eliminating beneficial effectsof the molecule. This effect arises from decreasing the level oractivity of a biomolecule such as IFNγ in cells that are dysregulated,while allowing normal immune cells to produce sufficient amounts of thesame molecule to perform normal immune functions. In locations where thebiomolecule is needed for activity, e.g., in lymph nodes or spleencells, sufficient amounts of the modulated molecule are present toelicit a desired response, while the level of the molecule in cells incirculation decreases. The compounds can increase IL-13, IL-15, IL-17 orIL-18 in conditions where a subject has a deficient Th1 immune response,e.g., in infection or cancer. Conversely, the compounds can decreaseIL-13, IL-15 or IL-18 in conditions such as allergy or autoimmuneconditions, e.g., multiple sclerosis, where an excess Th1 immune statusmay prevail.

In general, the F1Cs will detectably decrease the synthesis or one ormore biological activity of one or more of these molecules (or othertranscription factors or receptors disclosed herein) when such synthesisor activities is associated with the establishment, maintenance,progression or enhanced severity of a clinical condition or symptomdisclosed herein. Conversely, the F1Cs will generally detectablyincrease the synthesis or one or more biological activities of one ormore of these molecules (or other transcription factors or receptorsdisclosed herein) when such synthesis or activity is associated with thetreatment, prevention, cure or amelioration of a clinical condition orsymptom disclosed herein.

These decreases or increases compared to suitable controls can berelatively small, including changes near the lower limits ofdelectability for such molecules using known or new assays, e.g., adecrease or increase in the synthesis or biological activity of at leastabout 2%, about 5%, about 10% or about 20%. Such changes can be modestor relatively large, e.g., at least about a 50% change, at least about a90% change, or at least about a 200% change, up to about a 5-fold, abouta 10-fold, about a 100-fold or greater decrease or increase in thesynthesis or biological activity of the affected molecule(s) compared tosuitable controls. These changes are typically measured relative tocontrols that lack a F1C or that use known agonists or antagonists ofone or more relevant molecules. Assays can be based on measuringdecreases or increases in, e.g., one or more of protein levels, RNA ormRNA levels, a ligand binding activity, transcription of a targetgene(s) and the like. Suitable assay protocols include any suitablepolymerase chain reaction assay to measure an RNA or mRNA, any suitableblotting protocol for nucleic acid or for protein such as a Northern orWestern blot method or any transcription assay, including DNAfootprinting or a gene expression or gene function assay. Typically theF1Cs will effect detectable changes in the synthesis or one or morebiological activities in a concentration range of about 0.5×10⁻⁹ M toabout 3×10⁻⁵ M. Exemplary compositions that comprise a F1C for use in,e.g., in vivo animal assays, in vitro cell or tissue culture assays orin cell free assays, will comprise one or more suitable solvents orvehicles including DMSO, ethanol, water and a suitable tissue culturemedium.

One or more of these transcription factors, receptors or complexes canbe a component in methods when, e.g., they are used with a F1C incell-free assays or in tissue culture assays. Formation of thesecomplexes in cells or analysis of the effects of F1Cs on one or more oftheir biological activities is facilitated by inserting into the cells aDNA construct(s) that expresses one or more of these proteins, e.g.,mammalian or yeast cells containing a stable DNA construct or aconstruct used for transient transfection assays. Methods to performassays or to induce biological responses in vitro or in vivo using theF1Cs as agonists, antagonists or as reference standards are essentiallyas described, see, e.g., U.S. Pat. Nos. 5,080,139, 5,696,133, 5,932,431,5,932,555, 5,935,968, 5,945,279, 5,945,404, 5,945,410, 5,945,412,5,945,448, 5,952,319, 5,952,371, 5,955,632, 5,958,710, 5,958,892 and5,962,443; International Publication Numbers WO 96/19458, WO 99/41257and WO 99/45930. The complexes or assay systems, that comprise a F1C andone or more of these molecules are embodiments of the invention, as arethe use of these compositions when employed in the practice of any ofthe assay methods or in any of the clinical treatment methods disclosedherein or in the cited references.

Invention embodiments include a method comprising contacting a F1C(s)with a cell(s), whereby the F1C(s) forms a complex with a steroidhormone receptor or results directly or indirectly in the modulation ofa biological activity of the steroid hormone receptor or a gene that itregulates. The steroid hormone receptor may be an orphan nuclear hormonereceptor or a characterized receptor such as the glucocorticoidreceptor, estrogen receptor or the androgen receptor that displays amoderate or high binding affinity for the F1C(s). In some embodiments,the nuclear hormone receptor is a known receptor. Biological effectsfrom interaction of a F1C and a receptor can lead to interference withthe replication or development of a pathogen or the cell(s) itself,e.g., detectably inhibited proliferation of cancer cells. For example,expression of HIV transcripts in HIV-infected cells may be altered. Thereceptor-F1C complex may directly interfere with LTR-dependenttranscription of HIV genes, leading to reduced viral replication.Alternatively, such effects can include the decreased synthesis orbiological activity of a protein or gene product that is associated withthe establishment, maintenance or progression of a disease conditiondescribed herein or in the cited references.

An aspect of F1C biological activity is their capacity to modulate thecpacity of cells or tissues described herein to express one or moreenzymes that mediate phase II detoxification and reduction of damagingor reactive species such as xenobiotics, including electrophiles andchemical carcinogens, and superoxide radicals or hydrogen peroxide.Modulation of these genes is mediated by one or more transcriptionfactors or complexes of factors that include bZip transcription factorssuch as Nrf2 (NF-E2 related factor 2, Unigene symbol Nfe2L2) and Mafproteins such as MafG, MafK or MafF. These factors bind to cis-elementssuch as EpRE (electrophile response element) or ARE (antioxidentresponse element). EpRE and/or ARE elements present in the promoters ofphase II detoxification enzymes including NAD(P)H:quinineoxidoreductase-1 (NQO1) and glutathione-S-transferase (GST) as well ascellular defensive enzymes such as thioredoxins, heme oxygenase 1 (HO 1,or HMOX1), the catalytic and regulatory subunit γ-glutamylcycleinesyhthetase (γGCS or GCLM) and xCT (SLC7A11), a subunit of thecystine/glutamate exchange transporter. EpRE and ARE mediateupregulation of these genes following exposure of the cells to manyxenobiotics. In situations where enhanced expression of these genes ortranscription factors is desirable, the F1C upregulate the activity orlevels of one or more of these factors and/or enzymes.

Thus, in some embodiments the F1C are used to modulate the level oractivity of one or more of Nrf2, a thioredoxin, NQO1, GST, HO 1, thecatalytic subunit of γGCS, the regulatory subunit of γGCS and xCT incells or tissues that are exposed to a F1C. In some embodiments, thecells or tissues are treated with a F1C when an unwanted acute orchronic condition such as toxin exposure or elevated oxidative stress ispresent in the cells or tissues. Such conditions can occur, e.g., asdescribed elsewhere herein, including in acute or chronic pathologicalinflammation conditions, acute or chronic infections and traumaconditions. The effect of the F1Cs is restoration of normal expressionor establishment of desired levels of expression of one or more of thesetranscription factors or enzymes, e.g., decreased expression insituations where chronic over-expression occurs. Thus, the F1C can beused to modulate these or other genes described herein, e.g., todecrease expression or mRNA levels or protein levels of one or more ofthese or other genes in clinical conditions where excess or unwantedexpression or levels of the gene is associated with establishment,maintenance, severity or progression of the clinical condition resultingin clincal improvement in the disease or an unwanted symptom.

Homologs of these genes or proteins in other species, e.g., primates,are also modulated by the F1C. Modulation of these genes can beobserved, e.g., as increased expression or mRNA levels or protein levelsof the biomolecules in clinical conditions where insufficient orsuboptimal expression or levels of the gene is associated withestablishment, maintenance, severity or progression of the clinicalcondition to produce a desired clincal improvement.

Other therapeutic and biological applications and activities. The F1Csare useful for preventing, slowing the progression of or treatingcertain chronic conditions in a subject such as a mammal or a human.Chronic conditions include diseases and conditions that arise or developover a relatively long time period, e.g., over about 3 months to 10years or more. Such conditions include chronic renal failure, which mayresult from polycystic kidney disease, from, e.g., an autoimmunecondition such as acute or chronic glomerulonephritis, or from diabetes,interstitial nephritis, hypertension and other conditions discussedelsewhere herein. Chronic conditions include chronic pulmonaryconditions such as chronic bronchitis, lung fibrosis, right ventricularhypertrophy, pulmonary hypertension, emphysema, asthma and chronicobstructive pulmonary disease, which may be treated with a F1C. Theseconditions or their symptoms may be mild, moderate or severe. Thesubject may be suffering from the disease or condition or may be subjectto developing the condition, e.g., the subject may display early signsor a predisposition to develop a chronic condition. Such treatment willgenerally facilitate prevention of the disease, delay the onset orseverity of the disease or condition, ameliorate one or more symptoms,e.g., reduce shortness of breath, coughing or dyspnea, or slowprogression of the disease or condition. In these and other chronicconditions described herein, the F1Cs will generally be administered toa subject such as a human for a relatively long time period, e.g., forat least about 3 months to about 10 years or more. Dosages, routes ofadministration and dosing protocols for the F1Cs are essentially asdescribed herein. Dosing of the compound can be daily or intermittentusing a dosing protocol using dosages as described herein, e.g., about0.1 to about 20 mg/kg of a F1C administered to a subject once or twiceper day daily or intermittently. The use of the F1Cs can be combinedwith other treatments, e.g., β-agonists such as metaproterenol oralbuterol, or corticosteroids, e.g., prednisone, for asthma or chronicobstructive pulmonary disease.

The F1Cs can modulate the biological activity of cytokines orinterleukins that are associated with various immune deficiency ordysregulation conditions, which may be transient or chronic. They canthus be used to ameliorate, treat or prevent naturally occurringage-related decline in immune function in a subject or immune deficiencyor dysregulation resulting from trauma, stress, burns, surgery,autoimmunity or infections as described herein. Such immune deficiencydysregulation may be associated with, e.g., an age-related increase inproduction of one or more of IL-4, IL-5 and IL-6 or an age-relateddecrease in production of one or more of IL-2, IL-3, γ-IFN, GM-CSF orantibodies. In these embodiments, the F1C is administered to the subjectto detectably decrease production or levels of one or more of IL-4, IL-5and IL-6 or to detectably increase production or levels of one or moreof IL-2, IL-3, IL-5, IL-12, GM-CSF and γ-IFN. These cytokine changesfacilitate normalization of the subject's immune responses. Suchnormalization can be observed by various means. These means includemonitoring appropriate cytokine RNA or protein level(s) in the subjector by measuring biological responses such as restoration or detectableimprovement of contact hypersensitivity in a subject with depressed orsuboptimal contact hypersensitivity response. The F1Cs can thus be usedto enhance or restore a deficient or suboptimal immune response such ascontact hypersensitivity response in a subject with a chronic ortransient state of immune deficiency or dysregulation. In theseembodiments, the F1C is administered using the dosages, routes ofadministration and dosing protocols for the F1Cs essentially asdescribed herein. Treatment with the F1Cs is optionally combined withother appropriate treatments or therapies essentially as describedherein, e.g., a antibacterial or antiviral agent(s) is coadministeredwith a F1C to treat, prevent or ameliorate an infection in an infectedsubject or a subject suffering from, e.g., a burn. Methods to measurechanges in cytokine levels or contact hypersensitivity are known and canoptionally be applied in these embodiments, see, e.g., U.S. Pat. Nos.5,919,465, 5,837,269, 5,827,841, 5,478,566.

The capacity of the F1Cs to modulate immune functions permits their usefor treating, preventing, slowing the progression of or alleviating thea symptom(s) of subjects with psychological disorders, metabolicdisorders, chronic stress, sleep disorders, conditions associated withsexual senescence, aging, or premature aging. Metabolic disordersinclude parathyroidism, pseudoparathyroidism, hypoparathyroidism,hypercalcemia, hypocalcemia and detectable symptoms thereof such asfatigue, constipation, kidney stones and kidney malfunction. Chronicstress and related disorders include fibromyalgia, chronic fatiguesyndrome, hypothalamic-pituitary axis dysregulation. Other relatedpathological conditions that can be treated with the F1Cs includehormone deficiency associated with aging or with a pathologicalcondition, hypogonadism, vaginal atrophy, diminished libido, urinaryincontinence, skin collagen loss, loss or impairment of skin, organ orjoint connective tissue and menopause or its symptoms such as hotflashes, unwanted mood changes, fatigue and insomnia. In theseembodiments, treatment of subjects with a F1C is optionally combinedwith other suitable agents such as triiodothyronine, tetraiodothyronine,an insulin-like growth factor, insulin-like growth factor bindingprotein-3, an estrogen or a progestin.

As noted above, in some embodiments a treatment with a F1C is combinedwith a corticosteroid or glucocorticoid. Corticosteroids are used in anumber of clinical situations to, e.g., decrease the intensity orfrequency of flares or episodes of inflammation or autoimmune reactionsin conditions such as acute or chronic rheumatoid arthritis, acute orchronic osteoarthritis, ulcerative colitis, acute or chronic asthma,bronchial asthma, psoriasis, systemic lupus erythematosus, hepatitis,pulmonary fibrosis, type I diabetes, type II diabetes or cachexia.However, many corticosteroids have significant side effects ortoxicities that can limit their use or efficacy. The F1Cs are useful tocounteract such side effects or toxicities without negating all of thedesired therapeutic capacity of the corticosteroid. This allows thecontinued use, or a modified dosage of the corticosteroid, e.g., anincreased dosage, without an intensification of the side effects ortoxicities or a decreased corticosteroid dosage. The side-effects ortoxicities that can be treated, prevented, ameliorated or reducedinclude one or more of bone loss, reduced bone growth, enhanced boneresorption, osteoporosis, immunosuppression, increased susceptibility toinfection, mood or personality changes, depression, headache, vertigo,high blood pressure or hypertension, muscle weakness, fatigue, nausea,malaise, peptic ulcers, pancreatitis, thin or fragile skin, growthsuppression in children or preadult subjects, thromboembolism,cataracts, and edema. Dosages, routes of administration and dosingprotocols for the F1C would be essentially as described herein. Anexemplary dose of F1C of about 0.5 to about 20 mg/kg/day is administeredduring the period during which a corticosteroid is administered andoptionally over a period of about 1 week to about 6 months or more afterdosing with the corticosteroid has ended. The corticosteroids areadministered essentially using known dosages, routes of administrationand dosing protocols, see, e.g., Physicians Desk Reference 54^(th)edition, 2000, pages 323-2781, ISBN 1-56363-330-2, Medical EconomicsCo., Inc., Montvale, N.J. However, the dosage of the corticosteroid mayoptionally be adjusted, e.g., increased about 10% to about 300% abovethe normal dosage, without a corresponding increase in all of the sideeffects or toxicities associated with the corticosteroid. Such increaseswould be made incrementally over a sufficient time period and asappropriate for the subject's clinical condition, e.g., dailycorticosteroid dose increases of about 10% to about 20% to a maximum ofabout 300% over about 2 weeks to about 1 year.

Such corticosteroids include hydrocortisone (cortisol), corticosterone,aldosterone, ACTH, triamcinolone and derivatives such as triamcinolonediacetate, triamcinolone hexacetonide, and triamcinolone acetonide,betamethasone and derivatives such as betamethasone dipropionate,betamethasone benzoate, betamethasone sodium phosphate, betamethasoneacetate, and betamethasone valerate, flunisolide, prednisone,fluocinolone and derivatives such as fluocinolone acetonide, diflorasoneand derivatives such as diflorasone diacetate, halcinonide,dexamethasone and derivatives such as dexamethasone dipropionate anddexamethasone valerate, desoximetasone (desoxymethasone), diflucortoloneand derivatives such as diflucortolone valerate), flucloroloneacetonide, fluocinonide, fluocortolone, fluprednidene, flurandrenolide,clobetasol, clobetasone and derivatives such as clobetasone butyrate,alclometasone, flumethasone, and fluocortolone.

In some clinical conditions, the F1Cs can inhibit activated Tlymphocytes in vivo, and they can inhibit the expression or biologicalactivity of one or more of TNF-α, IFN-γ, IL-6, IL-8 or insulin likegrowth factor-1 receptor (IGF-1R) or IL-6 receptor. The compounds arethus useful to treat, prevent or ameliorate conditions where this is acomponent of pathology. Such conditions include inflammation conditionssuch as psoriasis, psoriatic arthritis, osteoarthritis, and rheumatoidarthritis. The compound can thus ameliorate the inflammation, e.g., byinhibiting expression of one or more of TNF-α, IFN-γ, IL-6, IL-8 orIGF-1R. Also, the compounds can inhibit unwanted T cell activity. Theycan thus ameliorate one or more psoriasis symptoms such as skin scaling,skin thickening, keratinocyte hyperproliferation, deficient filaggrinexpression (B. Baker et al., Br. J. Dermatol. 1984, 111:702), deficientstrateum corneum lipid deposition or they can improve a clinicalassessment such as the Psoriasis Activity and Severity Index. The F1Cscan be delivered to a subject with psoriasis using topical or systemicformulations as described herein. Topical formulations include gels,lotions and creams, e.g., as described herein. Daily or intermittentadministration of the compound can be used essentially as describedherein. The use of the F1Cs is optionally combined with one more currentpsoriasis treatments, e.g., topical emollients or moisturizers, tars,anthralins, systemic or topical corticosteroids, vitamin D analogs suchas calcitriol, methotrexate, etretinate, acitretin, cyclosporin, FK 506,sulfasalazine, ultraviolet B radiation optionally combined with one ormore of a topical corticosteroid, tar, anthralin, emollient ormoisturizer or ultraviolet A plus psoralen. Such additional treatmentsessentially would use known dosages and routes of administration, whichare applied, e.g., within a month before, during or within a month aftera treatment course with a F1C.

SPECIFIC EMBODIMENTS

Aspects of the invention and related subject matter include thefollowing specific embodiments and are not intended to limit theinvention in any way.

1A. A compound having the structure

or a salt thereof, provided that if a double bond is present at the 4-5-or 5-6-positions, then —H at the 5-position is absent and is otherwisepresent in the α- or β-configuration or if a double bond is present atthe 1-2-, 4-5- or 5-6-positions, then R^(10A), R^(10B) or R^(10C),respectively, are bonded to the ring to which they are linked by asingle bond;

wherein one each of R¹, R² and R³ is —H; one of R⁴ is —H or anoptionally substituted alkyl group; the other R¹ is —OH; the other R² is—H, —OH, —CH₃, a halogen or an alkoxy or both R² together are ═O or═CH₂; the other R³ is —H, halogen, —OH or an ester or both R³ togetherare ═O or ═CH₂; the other R⁴ is —NH₂, —N(R^(PR))₂, an optionallysubstituted amine moiety, an optionally substituted amide group, anN-linked amino acid or both R⁴ together are ═N—OH or ═NO-optionallysubstituted alkyl; R⁶ is —H or —CH₃; R⁷ is —CH(R¹⁰)₂— or ═CH(R¹⁰)—; R⁸and R⁹ independently are —C(R¹⁰)₂—; R¹⁰ independently are —H, —OH, anester, an alkoxy group or a halogen; R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, an optionally substituted alkyl group, ahalogen, —OR^(PR), —SR^(PR) or ═O; R^(PR) independently are —H or aprotecting group; wherein the protecting group defines —OR^(PR) as anester or an alkoxy group;

wherein (1) R^(10A) in R^(10A) and R^(10B), R^(10A) and R^(10C) orR^(10A) and R^(10D) is an optionally substituted alkyl group, a halogen,an ester, an alkoxy group, —OR^(PR), —SR^(PR) or ═O, and the otherR^(10B), R^(10C) or R^(10D) are as defined, (2) R^(10B) and R^(10C),R^(10B) and R^(10B) or R^(10C) and R^(10D) independently are anoptionally substituted alkyl group, a halogen, —OR^(PR), —SR^(PR) or ═O,or (3) one R² is as defined and the other R² is —OH, —CH₃, a halogen oran alkoxy group or both R² together are ═O; one R³ is as defined and theother R³ is a halogen, —OH or an ester or both R³ together are ═O; and

wherein the optionally substituted alkyl groups independently are —CH₃,—CH₂CH₃, —CH₂OH, or —CH₂— (ester), the alkoxy groups independently are—OCH₃, —OC₂H₅ or —OC₃H₇, the esters independently are a hydroxyl ester.

2A. The compound of embodiment 1A wherein R¹⁰, R^(10A), R^(10B), R^(10C)and R^(10D) independently are —H, an optionally substituted alkyl group,a halogen, —OH or an alkoxy group, wherein

(1) R^(10A) in R^(10A) and R^(10B), R^(10A) and R^(10C) or R^(10A) andR^(10D) is an optionally substituted alkyl group, a halogen, —OH or analkoxy group and the other R^(10B), R^(10C) or R^(10D) is as defined, or(2) R^(10B) and R^(10C), R^(10B) and R^(10C) or R^(10C) and R^(10D)independently are an optionally substituted alkyl group, a halogen, —OHor an alkoxy group.

3A. The compound of embodiment 1A wherein R¹⁰, R^(10A), R^(10B), R^(10C)and R^(10D) independently are —H, an optionally substituted alkyl group,a halogen, —OH, an alkoxy group or an ester, wherein the optionallysubstituted alkyl group is —CH₃ or —CH₂CH₃, the halogen atom is —F, —Clor —Br, the alkoxy group is —OCH₃ or —OC₂H₅ and the ester is —O—C(O)—CH₃or —O—C(O)—CH₂CH₃, wherein

(1) R^(10A) in R^(10A) and R^(10B), R^(10A) and R^(10C) or R^(10A) andR^(10D) is —CH₃, —CH₂CH₃, —F, —Cl, —Br, —OCH₃, —OC₂H₅, —O—C(O)—CH₃ or—O—C(O)—CH₂CH₃ and the other R^(10B), R^(10C) or R^(10D) is as defined,or (2) R^(10B) and R^(10C), R^(10B) and R^(10D) or R^(10C) and R^(10D)independently are —CH₃, —CH₂CH₃, —F, —Cl, —Br, —OCH₃, —OC₂H₅,—O—C(O)—CH₃ or —O—C(O)—CH₂CH₃.

4A. The compound of embodiment 1A wherein R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, —F, —Cl, —Br, —OH, —OCH₃, —OC₂H₅ or anester, wherein

(1) R^(10A) in R^(10A) and R^(10B), R^(10A) and R^(10C) or R^(10A) andR^(10D) is —F, —Cl, —Br, —OH, —OCH₃, —OC₂H₅ or an ester and the otherR^(10B), R^(10C) or R^(10D) is as defined, or (2) R^(10B) and R^(10C),R^(10B) and R^(10D) or R^(10C) and R^(10D) independently are —F, —Cl,—Br, —OH, —OCH₃, —OC₂H₅ or an ester.

5A. The compound of embodiment 1A wherein R¹⁰, R^(10A), R^(10B), R^(10C)and R^(10D) independently are —H, α-OH, β-OH or ═O, wherein (1) R^(10A)in R^(10A) and R^(10B), R^(10C) and R^(10D) or R^(10A) and R^(10D) isα-OH, β-OH or ═O and the other R^(10B), R^(10C) or R^(10D) is asdefined, or (2) R^(10B) and R^(10C), R^(10B) and R^(10D) or R^(10C) andR^(10D) independently are α-OH, β-OH or ═O.

6A. The compound of embodiment 1A wherein R⁷, R⁸, R⁹ independently are—C(R¹⁰)₂— or ═C(R¹⁰)— wherein one R¹⁰ is —H, —OH, an ester, an alkoxygroup or a halogen, in the α- or β-configuration, and the other R¹⁰, ifpresent, is —H.

7A. The compound of embodiment 1A wherein R⁷ and R⁸ independently are—CH₂—, —CF₂—, —CH(OH)—, —CH(R¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)-, wherein —OH, R¹⁰, the ester, the alkoxy group or thehalogen atom is present in the α-configuration; wherein the halogen atomis —F, —Cl or —Br, the alkoxy group is —OCH₃, —OC₂H₅ or —OC₃H₇ and theester is —OC(O)—CH₃ or —OC(O)CH₂CH₃.

8A. The compound of embodiment 1A wherein the other R² is —H, —OH or analkoxy group, wherein the alkoxy group is —OCH₃, or both R² together are═O; the other R³ is —H, halogen, —OH or an ester, wherein the ester is—O—C(O)—CH₃ or —O—C(O)—CH₂CH₃, or both R³ together are ═O; the other R⁴is an optionally substituted amine moiety or an optionally substitutedamide group; R⁶ is —H or —CH₃; R⁷ is —CH(R¹⁰)₂— or ═CH(R¹⁰)— and R⁸ andR⁹ independently are —C(R¹⁰)₂, wherein R¹⁰ independently are —H, —OH ora halogen; R^(10A) is halogen or R^(10A) and R^(10B), R^(10A) andR^(10C) or R^(10A) and R^(10D), R^(10B) and R^(10C), R^(10B) and R^(10D)or R^(10C) and R^(10D) independently are —OH or a halogen; and whereinthe halogens independently are —F, —Cl or —Br.

9A. The compound of embodiment 1A wherein the hydroxyl ester is acetate,enanthate, propionate, isopropionate, isobutyrate, butyrate, valerate,caproate, isocaproate, hexanoate, heptanoate, octanoate, nonanoate,decanoate, undecanoate, phenylacetate or benzoate.

10A. The compound of embodiment 1A wherein the compound has thestructure

wherein R¹ is —OH; R² is —OH, an alkoxy group or ═O; R³ is a halogen,—OH, an ester or ═O; and R⁴ is an optionally substituted amine moiety or═NOH.

11A. The compound of embodiment 10A wherein R¹ and R² are —OH; R³ is—OH, ═O, a halogen or an ester, wherein the halogen atom is —F or —Brand the ester is —O—C(O)—CH₃ or —O—C(O)—CH₂CH₃; and R⁴ is an optionallysubstituted amine moiety, wherein the optionally substituted aminemoiety is —NH₂, —NHCH₃, —N(CH₃)₂, —N⁺(CH₃)₃, —NH—C₂H₅ or —NHOH, or anoptionally substituted amide group, wherein the optionally substitutedamide group is —NH—C(O)CH₃.

12A. The compound of embodiment 11A wherein the compound has thestructure

13A. The compound of embodiment 11A wherein the compound has thestructure

14A. The compound of embodiment 1A wherein the compound is3β,7β-dihydroxy-6-chloro-16-oxo-17β-aminoandrost-5-ene,3β-hydroxy-6-chloro-16α-fluoro-17β-aminoandrost-5-ene,3β,7β-dihydroxy-6α-bromo-16-oxo-17β-aminoandrostane or3β-hydroxy-6α-bromo-16α-fluoro-17β-aminoandrostane.

15A. The compound of embodiment 1A wherein the compound is3β,7β-dihydroxy-16-oxo-17β-aminoandrost-5-ene or3β,7β-dihydroxy-16α-fluoro-17β-aminoandrostane.

16A. A formula 1 compound having the structure

or a salt thereof, provided that if a double bond is present at the 4-5or 5-6 positions, then R¹⁰ at the 5-position is absent and is otherwisepresent in the α- or β-configuration or if a double bond is present atthe 1-2, 4-5 or 5-6 positions, then R^(10A), R^(10B) or R^(10C)respectively are bonded to the ring to which they are linked by a singlebond;

wherein one of R¹ is —H, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl moiety or an optionallysubstituted heteroaryl moiety and the other R¹ is —OH, —OR^(PR),—O—Si—(R¹³)₃, —OSO₃H, —OPO₃H, an ester, an ether, a carbonate, acarbamate, an optionally substituted monosaccharide, an optionallysubstituted disaccharide or an optionally substituted oligosaccharide orboth of R¹ together are ═O or both R¹ comprise a ketal or thioketal; R²and R³ independently are —H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester, anether, a carbonate, a carbamate, a halogen, an optionally substitutedalkyl group, an optionally substituted alkenyl group, an optionallysubstituted alkynyl group, an optionally substituted aryl moiety or anoptionally substituted heteroaryl moiety or both of R² or R³ togetherare ═O or both of R² or R³ comprise an independently selected ketal orthioketal; one R⁴ is —H, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup or an optionally substituted aryl moiety and the other R⁴ is anoptionally substituted N-linked heterocycle; R⁵ and R⁶ independently are—H, —OH, —OR^(PR), an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety; or an optionally substitutedheteroaryl moiety; R⁷, R⁸ and R⁹ independently are —C(R¹⁰)₂—, ═O(R¹⁰)—,—O—, —S— or —NR^(PR)—, wherein R¹⁰ are independently selected; R¹⁰independently or together are —H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester,an ether, a carbonate, a carbamate, a halogen, —SR^(PR), an optionallysubstituted alkyl group, an optionally substituted alkenyl group, anoptionally substituted alkynyl group, an optionally substituted arylmoiety or an optionally substituted heteroaryl moiety or ═O; wherein R¹⁰moieties at the 5 (if present), 8, 9 and 14 positions independently are—H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester, an ether, a carbonate, acarbamate or a halogen; R^(10A), R^(10B), R^(10C) and R^(10D)independently are —H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester, an ether, acarbonate, a carbamate, a halogen, —SR^(PR), an optionally substitutedalkyl group, an optionally substituted alkenyl group, an optionallysubstituted alkynyl group, an optionally substituted aryl moiety or anoptionally substituted heteroaryl moiety or ═O or R^(10A), R^(10B),R^(10C) or R^(10D) is ═O; R¹³ independently are are a C1-C6 alkyl groupor an aryl moiety; and R^(PR) independently are —H or a protectinggroup; and

wherein (1) when the double bonds at the 1-2-, 4-5- and 5-6 positionsare absent (i) one R² is as defined and the other R² is —OH, —OR^(PR),—O—Si—(R¹³)₃, an ester, an ether, a carbonate, a carbamate, both R²together are ═O or both R² comprise a ketal or thioketal, (ii) one ofR^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A) and R^(10D), R^(10B)and R^(10C), R^(10B) and R^(10D) or R^(10C) and R^(10D) are anoptionally substituted alkyl group, —CH₃, —OH, —OR^(PR), —O—Si—(R¹³)₃,an ester, an ether, a carbonate, a carbamate, a halogen, —SR^(PR) or ═Oand the other R^(10A), R^(10B), R^(10C) or R^(10D) are as defined, or(2) when a double bond at the 1-2-, 4-5- or 5-6 position is present (i)one R² or one R³ is as defined and the other R² or R³ is —OH, —OR^(PR),—O—Si—(R¹³)₃, an ester, an ether, a carbonate, a carbamate, both R² orR³ together are ═O or both R² or R³ comprise a ketal or thioketal, (ii)one of R^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A) and R^(10D),R^(10B) and R^(10C), R^(10B) and R^(10D) or R^(10C) and R^(10D) are anoptionally substituted alkyl group, —CH₃, —OH, —OR^(PR), —O—Si—(R¹³)₃,an ester, an ether, a carbonate, a carbamate, a halogen, —SR^(PR) or ═Oand the other R^(10A), R^(10B), R^(10C) or R^(10D) are as defined.

17A. The compound of embodiment 16A wherein one each of R¹, R², R³ andR⁴ are —H, and, when no double bond links the other R¹, R², R³ and R⁴ tothe ring to which it is bonded, then the other R¹, R², R³ and R⁴respectively are in the α,α,α,α-, α,α,α,β-, α,α,β,α-, α,β,α,α-,β,α,α,α-, α,α,β,β-, α,β,α,β-, β,α,α,β-, β,α,β,α-, β,β,α,α-, α,β,β,α-,α,β,β,β-, β,α,β,β-, β,β,α,β-, β,β,β,α- or β,β,β,β-configurations; theother R¹, R² independently are —OH, —OCH₃, —OC₂H₅, a carbamate, acarbonate, an optionally substituted C1-C20 ether, an optionallysubstituted C1-C20 ester, an optionally substituted C1-C20monosaccharide, an optionally substituted disaccharide or an optionallysubstituted oligosaccharide; and the other R³ is —H, —F, —Cl, —Br, —I,—OH, —CH₃, —C₂H₅, —C(CH₃)₃, —OCH₃, —OC₂H₅, —CF₃, —CH₂OH, a carbamate, acarbonate, an optionally substituted C1-C20 alkyl group, an optionallysubstituted C1-C20 ether or an optionally substituted C1-C20 ester.

18A. The compound of embodiment 16A or 17A wherein the compound has thestructure

19A. The compound of embodiment 16A, 17A or 18A wherein (1) R⁵ and R⁶respectively are in the α,α-, α,β-, β,α- or β,β-configurations and R⁵and R⁶ are both —CH₃ or are selected from —CH₃ and —CH₂OH or (2) R⁵ andR⁶ are both in the β-configuration and R⁵ and R⁶ are both —CH₃ or areselected from —CH₃ and —CH₂OH.

20A. The compound of any one of embodiments 16 through 19 wherein 1R¹⁰at the 5, 8, 9 and 14-positions respectively are

(1) —H, —H, —H, —H, (2) —H, —H, halogen (—F, —Cl, —Br or —I), —H, (3)—H, —H, —H, —OH, (4) —H, —H, halogen (—F, —Cl, —Br or —I), —OH,(5)—optionally substituted alkyl (optionally —CH₃, —CH₂OH, —CH₂O-ester,—C₂H₅), —H, —H, —H, (6)—optionally substituted alkyl (optionally —CH₃,—CH₂OH, —CH₂O-ester, —C₂H₅), —H, halogen (—F, —Cl, —Br or —I), —H,(7)—optionally substituted alkyl (optionally —CH₃, —CH₂OH, —CH₂O-ester,—C₂H₅), —H, —H, —OH, (8)—acyl (optionally —C(O)—(CH₂)₀₋₂—CH₃), —H, —H,—H, (9)—ester (optionally acetoxy or propionoxy), —H, —H, —H, (10)—ether(optionally —O—(CH₂)₀₋₂—CH₃), —H, —H, —H, (11)—ester (optionallyacetoxy, propionoxy, —O—C(O)—(CH₂)₁₋₆—H), —H, halogen (optionally —F,—Cl, —Br), —H, (12)—ester (optionally acetoxy or propionoxy), —H, —H,—OH, (13) —H, —H, —H, -acyl (optionally —C(O) —(CH₂)₀₋₂—CH₃), (14) —H,—H, —H, -ester (optionally acetoxy or propionoxy), or (15) —H, —H, —H,-ether (optionally —O—(CH₂)₀₋₂—CH₃, —OCH₃, —OC₂H₅, —OCH₂OH, —OCH₂F,—OCH₂Br, —OCH₂COOH, —OCH₂NH₂, —OCH₂CH₂OH, —OCH₂CH₂F, —OCH₂CH₂Br,—OCH₂CH₂COOH or —OCH₂CH₂NH₂).

21A. The compound of any one of embodiments 16A through 20A wherein R⁷is —CH₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)-wherein hydroxyl, the ester, the alkoxy group or the halogen atom ispresent in the α-configuration and the alkoxy group is optionallyselected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl,—Br or —I.

22A. The compound of any one of embodiments 16A through 21A wherein R⁸is —CH₂—, —CF₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)- wherein hydroxyl, the ester, the alkoxy group or thehalogen atom is present in the α-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I.

23A. The compound of embodiment 16A wherein the compound has thestructure

R¹ is —OH, ═O, an ester or an ether; R² is —H, —OH, ═O, an ester or anether; R³ is —H, an optionally substituted alkyl group, a halogen, —OH,an ester or an ether; and one R⁴ is —H and other R⁴ is an optionallysubstituted N-linked heterocycle moiety.

24A. The compound of embodiment 23A wherein R⁵ and R⁶ independently are—H, —CH₃ or —CH₂OH; R⁷, R⁸ and R⁹ are —CH₂—; and R^(10A) and R^(10B)independently are an optionally substituted alkyl group, —CH₃, ahalogen, —SR^(PR) or —OR^(PR).

25A. The compound of embodiment 24A wherein the compound has thestructure

26A. The compound of embodiment 16A wherein the compound has thestructure

27A. The compound of embodiment 26A wherein R¹ is —OH, ═O, an ester oran ether; R² is —H, —OH, ═O, an ester or an ether; R³ is —H, anoptionally substituted alkyl group, a halogen, —OH, an ester or anether; and one R⁴ is —H and the other R⁴ is an optionally substitutedN-linked heterocycle moiety.

28A. The compound of embodiment 27A wherein R⁵ and R⁶ independently are—H, —CH₃ or —CH₂OH; R⁷, R⁸ and R⁹ are —CH₂—; and R^(10A) or R^(10B) is ahalogen, —SR^(PR) or —OR^(PR).

29A. The compound of embodiment 16A wherein the compound has thestructure

wherein one each of R¹ and R² are —H; the other R¹ and R² independentlyare —OH or an ester; one of R³ is —H and the other R³ is —OH, a halogen,an ester or both or R³ together are ═O; one R⁴ is —H and the other R⁴ isan optionally substituted N-linked heterocycle moiety; R⁵ is —CH₃,—CH₂CH₃ or —CH₂OH; R⁶ is —H, —CH₃ or —CH₂OH; and R⁷, R⁸ and R⁹ are—CH₂—.

30A. The compound of embodiment 29A wherein the compound has thestructure

31A. The compound of embodiment 30 wherein the optionally substitutedN-linked heterocycle moiety has the structure

wherein the dotted lines are optional double bonds; a is 0 or 1; —X— is—C(R¹⁰)₂—, ═C(R¹⁰)—, —O— or —N(R¹²)— provided the optional double bondsare absent when —X— is —N(R¹²)— or —O— or —X— is an amide or asulfonamide wherein the amide or sulfonamide nitrogen comprises theheterocycle ring and the double bond to X is not present; wherein R¹⁰ in—X— independently are —H, —OH, —OR^(PR), an ester or an ether and R¹² is—H, an optionally substituted alkyl group, formyl, an optionallysubstituted alkylsulfonyl moiety, an optionally substituted arylsulfonylmoiety, an optionally substituted aryl moiety or an optionallysubstituted heteroaryl moiety.

32A. The compound of embodiment 30A wherein the N-linked heterocyclemoiety is —N-pyrrolidine, —N1-pyrazolone, —N2-pyrazolone,—N-imidazolidin-2-one, —N1-imidazole, —N1-4,5-dihydroimidazole,—N-morpholine, —N-piperidine, —N-indole, —N-indoline, —N-quinolidine or—N1-piperazine, optionally substituted at N4 with an optionallysubstituted alkyl, aryl or heteroaryl moiety.

33A. A formula 1A compound having a structure of

provided that if a double bond is present at the 4-5 or 5-6 positions,then R¹⁰ at the 5-position is absent and is otherwise present in the α-or β-configuration or if a double bond is present at the 1-2, 4-5 or 5-6positions, then R^(10A), R^(10B) or R^(10C) respectively are bonded tothe ring to which they are linked by a single bond;

wherein one of R¹ is —H, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl moiety or an optionallysubstituted heteroaryl moiety and the other R¹ is —OH, —OR^(PR),—O—Si—(R¹³)₃, —OSO₃H, —OPO₃H, an ester, an ether, a carbonate, acarbamate, an optionally substituted monosaccharide, an optionallysubstituted disaccharide or an optionally substituted oligosaccharide;R² and R³ independently are —H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester,an ether, a carbonate, a carbamate, a halogen, an optionally substitutedalkyl group, an optionally substituted alkenyl group, an optionallysubstituted alkynyl group, an optionally substituted aryl moiety or anoptionally substituted heteroaryl moiety or both of R² or R³ togetherare ═O or both of R² or R³ comprise an independently selected ketal orthioketal; one R⁴ is —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester, an ether, acarbonate or a carbamate and the other R⁴ is an optionally substitutedC-linked heterocycle moiety; R⁵ and R⁶ independently are —H, —OH,—OR^(PR), an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety; or an optionally substitutedheteroaryl moiety; R⁷, R⁸ and R⁹ independently are —C(R¹⁰)₂—, ═O(R¹⁰)—,—O—, —S— or —NR^(PR)—, wherein R¹⁰ are independently selected; R¹⁰independently or together are —H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester,an ether, a carbonate, a carbamate, a halogen, —SR^(PR), an optionallysubstituted alkyl group, an optionally substituted alkenyl group, anoptionally substituted alkynyl group, an optionally substituted arylmoiety or an optionally substituted heteroaryl moiety or ═O; wherein R¹⁰moieties at the 5 (if present), 8, 9 and 14 positions independently are—H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester, an ether, a carbonate, acarbamate or a halogen; R^(10A), R^(10B), R^(10C) and R^(10D)independently are —H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester, an ether, acarbonate, a carbamate, a halogen, —SR^(PR), an optionally substitutedalkyl group, an optionally substituted alkenyl group, an optionallysubstituted alkynyl group, an optionally substituted aryl moiety or anoptionally substituted heteroaryl moiety or ═O or R^(10A), R^(10B),R^(10C) or R^(10D) is ═O; R¹³ independently are a C1-C6 alkyl group oran aryl moiety; and R^(PR) independently are —H or a protecting group;

wherein (1) one of R^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A) andR^(10D), R^(10B) and R^(10C), R^(10B) and R^(10D) or R^(10C) and R^(10D)are an optionally substituted alkyl group, —CH₃, —OH, —OR^(PR),—O—Si—(R¹³)₃, an ester, an ether, a carbonate, a carbamate, a halogen,—SR^(PR) or ═O and the other R^(10A), R^(10B), R^(10D) or R^(10D) are asdefined, (2) one R² is as defined and the other R² is —OH, —OR^(PR),—O—Si—(R¹³)₃, an ester, an ether, a carbonate, a carbamate, both R² orR³ together are ═O or both R² or R³ comprise a ketal or thioketal, or(3) one or more of R⁷, R⁸ and R⁹ independently are —C(R¹⁰)₂— or═C(R¹⁰)—, wherein one R¹⁰ is —OH, a halogen, an optionally substitutedalkyl group, an ester or an ether and the other R¹⁰ is —H or anoptionally substituted alkyl group or both R¹⁰ together are ═O;

34A. The compound of embodiment 33A wherein one each of R¹, R², R³ andR⁴ are —H, and, when no double bond links the other R¹, R², R³ and R⁴ tothe ring to which it is bonded, then the other R¹, R², R³ and R⁴respectively are in the α,α,α,α-, α,α,α,β-, α,α,β,α-, α,β,α,α-,β,α,α,α-, α,α,β,β-, α,β,α,β-, β,α,α,β-, β,α,β,α-, β,β,α,α-, α,β,β,α-,α,β,β,β-, β,α,β,β-, β,β,α,β-, β,β,β,α or β,β,β,β-configurations; theother R¹, R² independently are —OH, —OCH₃, —OC₂H₅, a carbamate, acarbonate, an optionally substituted C1-C20 ether, an optionallysubstituted C1-C20 ester, an optionally substituted C1-C20monosaccharide, an optionally substituted disaccharide or an optionallysubstituted oligosaccharide; and the other R³ is —H, —F, —Cl, —Br, —I,—OH, —CH₃, —C₂H₅, —C(CH₃)₃, —OCH₃, —OC₂H₅, —CF₃, —CH₂OH, a carbamate, acarbonate, an optionally substituted C1-C20 alkyl group, an optionallysubstituted C1-C20 ether or an optionally substituted C1-C20 ester.

35A. The compound of embodiment 33A or 34A wherein the compound has astructure of

36A. The compound of embodiment 33A, 34A or 35A wherein (1) R⁵ and R⁶respectively are in the α,α-, α,β-, β,α- or β,β-configurations and R⁵and R⁶ are both —CH₃ or are selected from —CH₃ and —CH₂OH or (2) R⁵ andR⁶ are both in the β-configuration and R⁵ and R⁶ are both —CH₃ or areselected from —CH₃ and —CH₂OH.

37A. The compound of any one of embodiments 33A through 36A wherein R¹⁰at the 5, 8, 9 and 14-positions respectively are (1) —H, —H, —H, —H, (2)—H, —H, halogen (—F, —Cl, —Br or —I), —H, (3) —H, —H, —H, —OH, (4) —H,—H, halogen (—F, —Cl, —Br or —I), —OH, (5)—optionally substituted alkyl(optionally —CH₃, —CH₂OH, —CH₂O-ester, —C₂H₅), —H, —H, —H,(6)—optionally substituted alkyl (optionally —CH₃, —CH₂OH, —CH₂O-ester,—C₂H₅), —H, halogen (—F, —Cl, —Br or —I), —H, (7)—optionally substitutedalkyl (optionally —CH₃, —CH₂OH, —CH₂O-ester, —C₂H₅), —H, —H, —OH,(8)—acyl (optionally —C(O)—(CH₂)₀₋₂—CH₃), —H, —H, —H, (9)—ester(optionally acetoxy or propionoxy), —H, —H, —H, (10)—ether (optionally—O—(CH₂)₀₋₂—CH₃), —H, —H, —H,

(11)—ester (optionally acetoxy, propionoxy, —O—C(O)—(CH₂)₁₋₆—H), —H,halogen (optionally —F, —Cl, —Br), —H, (12)—ester (optionally acetoxy orpropionoxy), —H, —H, —OH, (13) —H, —H, —H, -acyl (optionally—C(O)—(CH₂)₀₋₂—CH₃), (14) —H, —H, —H, -ester (optionally acetoxy orpropionoxy), or (15) —H, —H, —H, -ether (optionally —O—(CH₂)₀₋₂—CH₃,—OCH₃, —OC₂H₅, —OCH₂OH, —OCH₂F, —OCH₂Br, —OCH₂COOH, —OCH₂NH₂,—OCH₂CH₂OH, —OCH₂CH₂F, —OCH₂CH₂Br, —OCH₂CH₂COOH or —OCH₂CH₂NH₂).

38A. The compound of any one of embodiments 33A through 37A wherein R⁷is —CH₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)-wherein hydroxyl, the ester, the alkoxy group or the halogen atom ispresent in the α-configuration and the alkoxy group is optionallyselected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl,—Br or —I.

39A. The compound of any one of embodiments 33A through 38A wherein R⁸is —CH₂—, —CF₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)- wherein hydroxyl, the ester, the alkoxy group or thehalogen atom is present in the α-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I.

40A. The compound of embodiment 33A wherein the compound has a structure

wherein R¹ is —OH, ═O, an ester or an ether; R² is —H, —OH, ═O, an esteror an ether; R³ is —H, an optionally substituted alkyl group, a halogen,—OH, an ester or an ether; one R⁴ is —OH, an ester or an ether and theother R⁴ is an optionally substituted C-linked heterocycle moiety.

41A. The compound of embodiment 40 wherein R⁵ and R⁶ independently are—H, —CH₃ or —CH₂OH; R⁷, R⁸ and R⁹ are —CH₂—; and R^(10A), R^(10B),R^(10C) and R^(10D) independently are an optionally substituted alkylgroup, —CH₃, a halogen, —SR^(PR) or —OR^(PR).

42A. The compound of embodiment 41A wherein the compound has thestructure

43A. The compound of embodiment 41A wherein the compound has thestructure

44A. The compound of embodiment 42A or 43A wherein R¹ is —OH or ═O; R²is —OH, ═O or an ether wherein the ether is —OCH₃; R³ is —H, a halogenor an ester wherein the ester is —O—C(O)CH₃ or —O—C(O)CH₂CH₃; one R⁴ isan optionally substituted C-linked heterocycle moiety, wherein theC-linked heterocycle is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl,6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-thiazolyl,4-thiazolyl or 5-thiazolyl and the other R⁴ is —OH; and R^(10A),R^(10B), R^(10C) or R^(10D) is —H, —OR^(PR) or a halogen.

45A. The compound of embodiment 44A wherein R¹ and R² are —OH; R³ is —Hor —O—C(O)CH₃; R⁴ is 3-pyridyl; and R^(10A) or R^(10B) is —OR^(PR) or—F.

46A. A formula 1 compound having the structure

or a salt thereof; wherein the dotted lines are optional double bonds;R¹⁰ at the 5 (if present), 8, 9 and 14 positions respectively are in theα,α,α,α-, α,α,α,β-, α,α,β,α-, α,β,α,α-, β,α,α,α-, α,α,β,β-, α,β,α,β-,β,α,α,β-, βα,β,α-, β,β,α,α-, α,β,β,α-, α,β,β,β-, β,α,β,β-, β,β,α,β-,β,β,β,α- or β,β,β,β-configurations; R^(10A) and R^(10B), R^(10A) andR^(10C), R^(10A) and R^(10D), R^(10B) and R^(10C), R^(10B) or R^(10D)and R^(10C) respectively are in the α,α-, α,β-, β,α- orβ,β-configurations, provided that if a double bond is present at the 4-5or 5-6 positions, then R¹⁰ at the 5-position is absent and is otherwisepresent in the α- or β-configuration or if a double bond is present atthe 1-2, 4-5 or 5-6 positions, then R^(10A), R^(10B) or R^(10C)respectively are bonded to the ring to which they are linked by a singlebond;

one of R¹ is —H, an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety or an optionally substitutedheteroaryl moiety and the other R¹ is —OH, —OR^(PR), —SR^(PR),—O—Si—(R¹³)₃, —OSO₃H, —OPO₃H, an ester, an ether, a carbonate, acarbamate, an optionally substituted monosaccharide, an optionallysubstituted disaccharide or an optionally substituted oligosaccharide orboth of R¹ together are ═O or both R¹ comprise a ketal or thioketal; R²and R³ independently are —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, anester, an ether, a carbonate, a carbamate, a halogen, an optionallysubstituted alkyl group, an optionally substituted alkenyl group, anoptionally substituted alkynyl group, an optionally substituted arylmoiety or an optionally substituted heteroaryl moiety or both of R² orR³ together are ═O or both of R² or R³ comprise an independentlyselected ketal or thioketal; R⁴ is an optionally substituted N-linkedheterocycle moiety, an optionally substituted amine moiety, anoptionally substituted amide group or an optionally substituted C-linkedheterocycle moiety; R⁵ and R⁶ independently are —H, —OH, —OR^(PR), anoptionally substituted alkyl group, an optionally substituted alkenylgroup, an optionally substituted alkynyl group, an optionallysubstituted aryl moiety; or an optionally substituted heteroaryl moiety;R⁷, R⁸ and R⁹ independently are —C(R¹⁰)₂—, ═C(R¹⁰)—, —O—, —S— or—NR^(PR)—, wherein R¹⁰ are independently selected; R¹⁰ independently ortogether are —H, —OH, —OR^(PR), —O—Si—(R¹³)₃, an ester, an ether, acarbonate, a carbamate, a halogen, —SR^(PR), an optionally substitutedalkyl group, an optionally substituted alkenyl group, an optionallysubstituted alkynyl group, an optionally substituted aryl moiety or anoptionally substituted heteroaryl moiety or ═O; wherein R¹⁰ moieties atthe 5 (if present), 8, 9 and 14 positions are —H, —OH, —OR^(PR),—O—Si—(R¹³)₃, an ester, an ether, a carbonate, a carbamate or a halogen;R^(10A), R^(10B), R^(10C) and R^(10D) independently are —H, —OH,—OR^(PR), —O—Si—(R¹³)₃, an ester, an ether, a carbonate, a carbamate,═O, a halogen, —SR^(PR), an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl moiety or an optionallysubstituted heteroaryl moiety or ═O; R¹³ independently are a C1-C6 alkylgroup or an aryl moiety; and R^(PR) independently are —H or a protectinggroup;

wherein when R⁹ is —CH₂— or ═CH—, R⁷ or R⁸ is —CH₂—, —CH(OH)— or —C(O)—,R⁵ and R⁶ are —CH₃ and (1) R⁴ is an optionally substituted C-linkedheterocycle moiety and R³ is —H or an ether, or (2) R⁴ is an optionallysubstituted N-linked heterocycle moiety and R³ is —H or an optionallysubstituted alkyl group, then (i) one R² is as defined an the other R²is —OH, an ester, an ether, a carbonate or a carbamate or both R²together are ═O or both R² comprise a ketal or thioketal or (ii) one ofR^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A) and R^(10D), R^(10B),and R^(10C), R^(10B) and R^(10D) or R^(10C) and R^(10D) is a halogen,—SR^(PR) or —OR^(PR) and the other R^(10A), R^(10B), R^(10C) or R^(10D)are as defined.

47A. The compound of embodiment 46A wherein one each of R¹, R² and R³are —H, and, when no double bond links the other R¹, R² and R³ to thering to which it is bonded, then the other R¹, R² and R³ respectivelyare in the α,α,α-, α,α,β-, α,β,α-, β,α,α-, β,α,β-, β,β,α-, α,β,β- orβ,β,β-configurations; the other R¹, R² independently are —OH, —OCH₃,—OC₂H₅, a carbamate, a carbonate, an optionally substituted C1-C20ether, an optionally substituted C1-C20 ester, an optionally substitutedC1-C20 monosaccharide, an optionally substituted disaccharide or anoptionally substituted oligosaccharide; and the other R³ is —H, —F, —Cl,—Br, —I, —OH, —CH₃, —C₂H₅, —C(CH₃)₃, —OCH₃, —OC₂H₅, —CF₃, —CH₂OH, acarbamate, a carbonate, an optionally substituted C1-C20 alkyl group, anoptionally substituted C1-C20 ether or an optionally substituted C1-C20ester.

48A. The compound of embodiment 46A or 47A wherein the compounds havethe structure

49A. The compound of embodiment 46A, 47A or 48A wherein (1) R⁵ and R⁶respectively are in the α,α-, α,β-, β,α- or β,β-configurations and R⁵and R⁶ are both —CH₃ or are selected from —CH₃ and —CH₂OH or (2) R⁵ andR⁶ are both in the β-configuration and R⁵ and R⁶ are both —CH₃ or areselected from —CH₃ and —CH₂OH.

50A. The compound of any one of embodiments 46A through 49A wherein R¹⁰at the 5, 8, 9 and 14-positions respectively are (1) —H, —H, —H, —H, (2)—H, —H, halogen (—F, —Cl, —Br or —I), —H, (3) —H, —H, —H, —OH, (4) —H,—H, halogen (—F, —Cl, —Br or —I), —OH,

(5)—optionally substituted alkyl (optionally —CH₃, —CH₂OH, —CH₂O-ester,—C₂H₅), —H, —H, —H, (6)—optionally substituted alkyl (optionally —CH₃,—CH₂OH, —CH₂O-ester, —C₂H₅), —H, halogen (—F, —Cl, —Br or —I), —H,(7)—optionally substituted alkyl (optionally —CH₃, —CH₂OH, —CH₂O-ester,—C₂H₅), —H, —H, —OH, (8)—acyl (optionally —C(O)—(CH₂)₀₋₂—CH₃), —H, —H,—H, (9)—ester (optionally acetoxy or propionoxy), —H, —H, —H, (10)—ether(optionally —O—(CH₂)₀₋₂—CH₃), —H, —H, —H, (11)—ester (optionallyacetoxy, propionoxy, —O—C(O)—(CH₂)₁₋₆—H), —H, halogen (optionally —F,—Cl, —Br), —H, (12)—ester (optionally acetoxy or propionoxy), —H, —H,—OH, (13) —H, —H, —H, -acyl (optionally —C(O)—(CH₂)₀₋₂—CH₃), (14) —H,—H, —H, -ester (optionally acetoxy or propionoxy), or (15) —H, —H, —H,-ether (optionally —O—(CH₂)₀₋₂—CH₃, —OCH₃, —OC₂H₅, —OCH₂OH, —OCH₂F,—OCH₂Br, —OCH₂COOH, —OCH₂NH₂, —OCH₂CH₂OH, —OCH₂CH₂F, —OCH₂CH₂Br,—OCH₂CH₂COOH or —OCH₂CH₂NH₂).

51A. The compound of any one of embodiments 46A through 50A wherein R⁷is —CH₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)-wherein hydroxyl, the ester, the alkoxy group or the halogen atom ispresent in the α-configuration and the alkoxy group is optionallyselected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl,—Br or —I.

52A. The compound of any one of embodiments 46A through 51A wherein R⁸is —CH₂—, —CF₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)- wherein hydroxyl, the ester, the alkoxy group or thehalogen atom is present in the α-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I.

53A. The compound of embodiment 46A wherein R¹ is —OH, ═O, an ester oran ether; R² is —H, —OH, ═O, an ester or an ether; R³ is —H, anoptionally substituted alkyl group, a halogen, —OH, an ester or anether; and R^(10A), R^(10B), R^(10C) and R^(10D) independently are —H, ahalogen, —SR^(PR) or —OR^(PR), wherein one of R^(10A) and R^(10B),R^(10A) and R^(10C), R^(10A) and R^(10D), R^(10B) and R^(10C), R^(10B)and R^(10D) or R^(10C) and R^(10D) is a halogen, —SR^(PR) or —OR^(PR) orR³ is a halogen, —OH or an ester when R² is —H.

54A. The compound of embodiment 53A wherein R⁵ and R⁶ independently are—H, —CH₃ or —CH₂OH; and R⁷, R⁸ and R⁹ are —CH₂—.

55A. The compound of embodiment 46A wherein the compound has thestructure

wherein one R¹ is —H and the other R¹ is —OH, an ester or an ether orboth R¹ together are ═O; one R² is —H, and the other R² is —H, —OH, anester or an ether or both R² together are ═O; R³ is —H, a halogen, —OH,an ester or an ether; R⁴ is an optionally substituted amine moiety, andoptionally substituted amide group, an optionally substituted N-linkedheterocycle moiety or an optionally substituted C-linked heterocyclemoiety; R⁵ and R⁶ independently are —H or an optionally substitutedalkyl group; R⁷, R⁸ and R⁹ independently are —C(R¹⁰)₂—, wherein R¹⁰independently or together are —H, —OH, ═O, an ester or an ether;R^(10A), R^(10B), R^(10C) and R^(10D) independently are —H, a halogen—SR^(PR) or —OR^(PR); and R^(PR) independently are —H or a protectinggroup;

wherein (1) when R⁴ is an optionally substituted N-linked heterocyclemoiety and R³ is —H or optionally substituted alkyl or (2) when R⁴ is anoptionally substituted C-linked heterocycle moiety and R³ is —H or anether, (i) one R² is as defined and the other R² is —OH, an ester or anether or (ii) one of R^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A)and R^(10D), R^(10B) and R^(10C), R^(10B) and R^(10D) or R^(10C) andR^(10D) is a halogen, —SR^(PR) or —OR^(PR).

56A. The compound of embodiment 55A wherein R⁵ and R⁶ independently are—H, —CH₃ or —CH₂OH; and R⁷, R⁸ and R⁹ are —CH₂— or ═CH—.

57A. The compound of embodiment 46 wherein the compound has thestructure

wherein, R¹ is —OH, ═O, —SH, an ester or an ether; R² is —OH, an esteror an ether; R³ is —H, a halogen, —OH, an ester or an ether; and R⁴ isan optionally substituted amine moiety, an optionally substituted amidegroup or an optionally substituted N-linked heterocycle moiety.

58A. The compound of embodiment 57A wherein the compound has thestructure

59A. The compound of embodiment 57A wherein the compound has thestructure

60A. The compound of embodiment 59A wherein R¹ is —OH, —SH or ═O; R² is—OH, ═O or —OCH₃; R³ is —H, —F, —Cl, —Br, —OH, —O—C(O)CH₃ or—O—C(O)CH₂CH₃; and R⁴ is an optionally substituted amine moiety or anoptionally substituted amide group wherein the amine moiety or amidegroup is —NH₂, —NHOH, —NH—C(O)CH₃, —NHCH₃ or —NH(CH₃)₂.

61A. The compound of embodiment 59A wherein R¹ is —OH, —SH or ═O; R² is—OH, ═O or —OCH₃; R³ is —H, —F, —Cl, —Br, —OH, —O—C(O)CH₃ or—O—C(O)CH₂CH₃; and R⁴ is an optionally substituted N-linked heterocyclemoiety, wherein the N-linked heterocycle moiety is —N-pyrrolidine,—N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N1-pyridine, —N-piperidine or—N-piperazine.

62A. The compound of embodiment 59A wherein R¹ is —OH, —SH or ═O; R² is—OH, ═O or —OCH₃; R³ is —H, —F, —Cl, —Br, —OH, —O—C(O)CH₃ or—O—C(O)CH₂CH₃; and R⁴ is an optionally substituted amide group or anoptionally substituted N-linked heterocycle moiety, wherein the N-linkedheterocycle moiety is —N-piperazine substituted at N4 with optionallysubstituted alkyl, —N-indole, —N-indoline, —N-quinolidine, and the amidegroup is —NH—C(O)—CH₂—CH₂—C(O)—OH, —NH—C(O)—CH₂—C(O)—OH,—NH—C(O)—CH₂—CH₂—C(O)—OR^(PR), —NH—C(O)—CH₂—C(O)—OR^(PR),—NH—C(O)—(CH₂)₃—C(O)—OH or —NH—C(O)—(CH₂)₃—C(O)—OR^(PR), wherein R^(PR)is a protecting group.

63A. The compound of embodiment 59A wherein R¹ is —OH, —SH or ═O; R² is—OH, ═O or —OCH₃; R³ is —H, —F, —Cl, —Br, —OH, —O—C(O)CH₃ or—O—C(O)CH₂CH₃; and R⁴ is an optionally substituted amine moiety whereinthe amine moiety is —NH—CH(CH₃)—C(O)OH, —NH—CH(CH₃)—C(O)OR^(PR),—NH—CH(CH₂OH)—C(O)OH, —NH—CH(CH₂OH)—C(O)OR^(PR), —NH—CH₂—CH₂—C(O)—OH,—NH—CH₂—C(O)—OH, —NH—CH₂—CH₂—C(O)—OR^(PR), —NH—CH₂—C(O)—OR^(PR),—NH—(CH₂)₃—C(O)—OH or —NH—(CH₂)₃—C(O)—OR^(PR), wherein R^(PR) is aprotecting group.

64A. The compound of embodiment 46A wherein the compound has thestructure

65A. The compound of embodiment 64A wherein R¹ is —OH or ═O; R² is —H,—OH or an ether wherein the ether is —OCH₃; R³ is —H, a halogen or anester wherein the ester is —O—C(O)CH₃ or —O—C(O)CH₂CH₃; R⁴ is anoptionally substituted N-linked heterocycle moiety, wherein the N-linkedheterocycle moiety is —N-pyrrolidine, —N1-pyrazolone, —N2-pyrazolone,—N-imidazolidin-2-one, —N1-imidazole, —N1-4,5-dihydroimidazole,—N-morpholine, —N-piperidine, —N-indole, —N-indoline, —N-quinolidine or—N1-piperazine, optionally substituted at N4 with optionally substitutedalkyl, aryl or heteroaryl; and R^(10A), R^(10B)R^(10C) or R^(10D) are—H, a halogen or —OR^(PR), wherein R^(10A), R^(10B)R^(10C) or R^(10D) isa halogen or —OR^(PR) or R³ is a halogen or an ester when R² is —H.

66A. The compound of embodiment 46A wherein the compound has thestructure

67A. The compound of embodiment 66A wherein R¹ is —OH or ═O; R² is —H,—OH or an ether wherein the ether is —OCH₃; R³ is —H or an ester whereinthe ester is —O—C(O)CH₃ or —O—C(O)CH₂CH₃; R⁴ is an optionallysubstituted N-linked heterocycle moiety, wherein the N-linkedheterocycle moiety is —N-pyrrolidine, —N1-pyrazolone, —N2-pyrazolone,—N-imidazolidin-2-one, —N1-imidazole, —N1-4,5-dihydroimidazole,—N-morpholine, —N-piperidine, —N-indole, —N-indoline, —N-quinolidine or—N1-piperazine, optionally substituted at N4 with optionally substitutedalkyl, aryl or heteroaryl; and R^(10A), R^(10B), R^(10C) or R^(10D) are—H, a halogen or —OR^(PR), wherein R^(10A), R^(10B), R^(10C) or R^(10D)is a halogen or —OR^(PR) when R² and R³ are —H.

68A. The compound of embodiment 46A wherein the compound has thestructure

wherein R¹ is —OH or ═O; R² is —H, —OH, ═O or an ether wherein the etheris —OCH₃; R³ is —H, a halogen or an ester wherein the ester is—O—C(O)CH₃ or —O—C(O)CH₂CH₃; R⁴ is an optionally substituted C-linkedheterocycle moiety, wherein the C-linked heterocycle moiety is2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-thiazolyl, 4-thiazolyl or5-thiazolyl; and R^(10A), R^(10B), R^(10C) or R^(10D) is —H, a halogen,—SR^(PR) or —OR^(PR); wherein R^(10A), R^(10B), R^(10C) or R^(10D) is ahalogen, —SR^(PR) or —OR^(PR) when R² and R³ are —H.

68A. The compound of embodiment 69A wherein R¹ and R² are —OH; R³ is —Hor —O—C(O)CH₃; R⁴ is 3-pyridyl; and R^(10A) or R^(10B) is —H, —OR^(PR)or —F.

69A. The compound of embodiment 46A wherein the compound is3β,16-dihydroxy-17-N-pyrrolidinylandrost-5,16-diene,3β,7β-dihydroxy-17-N-pyrrolidinylandrost-5,16-diene,3β-hydroxy-16α-fluoro-17β-N-pyrrolidinylandrost-1,16-diene.

70A. The compound of embodiment 46A wherein the compound is17-(3-pyridyl)-androst-1,5,16 triene-3β-ol or17-(3-pyridyl)-16-fluoro-androst-1,5,16 triene-3β-ol,3β,7β-dihydroxy-17-(3-pyridyl)-5α-androst-16-ene or3β,7β-dihydroxy-17-(3-pyridyl)-androst-5,16-diene.

71A. A compound having the structure

wherein one R⁴ is —OH, —NH₂, —NH—C(O)CH₃, —NHCH₃, —NH(CH₃)₂, —N⁺(CH₃)₃,—NH—CH₂CH₃, —NHOH or an N-linked heterocycle moiety, wherein theheterocycle moiety is —N-pyrrolidine, —N1-pyrazolone, —N2-pyrazolone,—N-imidazolidin-2-one, —N1-imidazole, —N1-4,5-dihydroimidazole,—N-morpholine, —N1-pyridine, —N-piperidine, —N-piperazine, —N-piperazinesubstituted at N⁴ with optionally substituted alkyl, —N-indole,—N-indoline, —N-quinolidine, and the other R⁴ is —H or both R⁴ togetherare ═O or ═NHOH.

72A. The compound of embodiment 71A wherein R¹ is in the α- orβ-configuration and is —OH; one R² is —OH and the other R² is —H or bothR² together are ═O; R³ is —H, halogen, —OH, —O—C(O)—CH₃ or—O—C(O)—CH₂CH₃; R⁴ in the β-configuration is —OH or an N-linkedheterocycle moiety, wherein the heterocycle moiety is pyrrollidine orpiperidine; R⁴ in the α-configuration is —H; R⁶ is —H or —CH₃; R^(10B)is halogen; and R^(10C) is halogen or —OR^(PR);

and wherein the halogens independently are —F, —Cl or —Br;

73A. The compound of embodiment 72 wherein the compound has thestructure

wherein R¹ is —OH; R³ is in the α- or β-configuration and is —H,halogen, —OH, —O—C(O)—CH₃ or —O—C(O)—CH₂CH₃; R⁴ in the β-configurationis —OH and R⁴ in the α-configuration is —H; R^(10B) is F, —Br or —Cl;and R^(10C) is halogen or —OR^(PR), wherein R^(PR) is —H.

74A. The compound of embodiment 73A wherein the compound has thestructure

75A. The compound of embodiment 74 wherein the compound is4α-fluoro-3β,6α,17β-trihydroxyandrostane.

1B. A formula 1 compound having the structure

or a salt thereof; wherein the dotted lines are optional double bondsand —H at the 5-position (if present) is in the α- or β-configuration orif a double bond is present at the 1-2, 4-5 or 5-6 positions, thenR^(10A), R^(10B) or R^(10C) respectively are bonded to the ring to whichthey are linked by a single bond; R^(10A) and R^(10B), R^(10A) andR^(10C), R^(10A) and R^(10D), R^(10B) and R^(10C), R^(10B) or R^(10D)and R^(10C) respectively are in the α,α-, α,β-, β,α- orβ,β-configurations;

wherein one of R¹ is —H, an optionally substituted alkyl group, anoptionally substituted alkenyl group or an optionally substitutedalkynyl group and the other R¹ is —OH, an ester, or an alkoxy group; R²and R³ independently are —H, —OH, an ester, an alkoxy group or ahalogen; R⁴ is an optionally substituted N-linked heterocycle moiety, anoptionally substituted amine moiety, an optionally substituted amidegroup or an optionally substituted C-linked heterocycle moiety, whereinthe C-linked heterocycle moiety is 2-pyridyl, 3-pyridyl, 4-pyridyl,5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl,6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,6-pyrimidinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl; R⁵ and R⁶independently are —H or an optionally substituted alkyl group, R⁷ is—C(R¹⁰)₂— and R⁸ and R⁹ independently are —C(R¹⁰)₂— or ═O(R¹⁰)—, whereinR¹⁰ are independently selected; R¹⁰, R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, halogen, —SR^(PR) or —OR^(PR); R^(PR)independently are —H or a protecting group, wherein R^(PR) of —OR^(PR)defines an ester or an alkoxy group;

wherein (1) one R² is as defined and the other R² is —OH, an ester, analkoxy group or a halogen or R³ is a halogen, an ester or an alkoxygroup, or (2) one of R^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A)and R^(10D), R^(10B) and R¹⁰, R^(10B) and R^(10D) or R^(10C) and R^(10D)is a halogen, —SR^(PR) or —OR^(PR) and the other R^(10A), R^(10B),R^(10C) or R^(10D) is as defined.

2B. The compound of embodiment 1B, wherein R⁷, R⁸ and R⁹ independentlyare —CH₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)-, wherein hydroxyl, the ester, the alkoxy group or thehalogen atom is present in the α-configuration and the alkoxy group is—OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl or —Br.

3B. The compound of embodiment 2B, wherein R¹ is —OH, an ester or analkoxy group; R² is —H, —OH, an ester or an alkoxy group; R³ is —H, ahalogen, —OH, an ester or an alkoxy group; and R^(10A), R^(10B), R^(10C)and R^(10D) independently are —H, a halogen or —OR^(PR),

wherein one of R^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A) andR^(10D), R^(10B) and R^(10C), R^(10B) and R^(10D) or R^(10C) and R^(10D)is a halogen or —OR^(PR) when R² is —H.

4B. The compound of embodiment 3B, wherein R⁵ and R⁶ independently are—H, —CH₃ or —CH₂OH; and R⁷, R⁸ and R⁹ are —CH₂—.

5B. The compound of embodiment 4B, wherein the compound has thestructure

wherein R¹ and R² independently are —OH, an ester or an alkoxy group; R³is —H, a halogen, —OH or an ester; and R⁴ is an optionally substitutedamine moiety, an optionally substituted amide group or an optionallysubstituted N-linked heterocycle moiety.

6B. The compound of embodiment 5B, wherein the compound has thestructure

7B. The compound of embodiment 5B, wherein the compound has thestructure

8B. The compound of embodiment 7B, wherein R¹ is —OH; R² is —OH or—OCH₃; R³ is —H, —F, —Cl, —Br, —OH, —O—C(O)CH₃ or —O—C(O)CH₂CH₃; and R⁴is an optionally substituted amine moiety or an optionally substitutedamide group, wherein the amine moiety or amide group is —NH₂, —NHOH,—NH—C(O)CH₃, —NHCH₃ or —NH(CH₃)₂.

9B. The compound of embodiment 7B, wherein R¹ is —OH; R² is —OH or—OCH₃; R³ is —H, —F, —Cl, —Br, —OH, —O—C(O)CH₃ or —O—C(O)CH₂CH₃; and R⁴is an optionally substituted N-linked heterocycle moiety, wherein theN-linked heterocycle moiety is —N-pyrrolidine, —N1-pyrazolone,—N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N1-pyridine, —N-piperidine or—N-piperazine.

10B. The compound of embodiment 7B, wherein R¹ is —OH; R² is —OH or—OCH₃; R³ is —H, —F, —Cl, —Br, —OH, —O—C(O)CH₃ or —O—C(O)CH₂CH₃; and R⁴is an optionally substituted amide group or an optionally substitutedN-linked heterocycle moiety, wherein the N-linked heterocycle moiety is—N-piperazine substituted at N4 with optionally substituted alkyl,—N-indole, —N-indoline or —N-quinolidine, and the amide group is—NH—C(O)—CH₂—CH₂—C(O)—OH, —NH—C(O)—CH₂—C(O)—OH,—NH—C(O)—CH₂—CH₂—C(O)—OR^(PR), —NH—C(O)—CH₂—C(O)—OR^(PR),—NH—C(O)—(CH₂)₃—C(O)—OH or —NH—C(O)—(CH₂)₃—C(O)—OR^(PR), wherein R^(PR)is a protecting group.

11B. The compound of embodiment 7B, wherein R¹ is —OH; R² is —OH or—OCH₃; R³ is —H, —F, —Cl, —Br, —OH, —O—C(O)CH₃ or —O—C(O)CH₂CH₃; and R⁴is an optionally substituted amine moiety, wherein the amine moiety is—NH—CH(CH₃)—C(O)OH, —NH—CH(CH₃)—C(O)OR^(PR), —NH—CH(CH₂OH)—C(O)OH,—NH—CH(CH₂OH)—C(O)OR^(PR), —NH—CH₂—CH₂—C(O)—OH, —NH—CH₂—C(O)—OH,—NH—CH₂—CH₂—C(O)—OR^(PR), —NH—CH₂—C(O)—OR^(PR), —NH—(CH₂)₃—C(O)—OH or—NH—(CH₂)₃—C(O)—OR^(PR), wherein R^(PR) is a protecting group.

12B. The compound of embodiment 1B, wherein the compound has thestructure

wherein R¹ is —OH; R² is —H, —OH or —OCH₃; R³ is —H, a halogen,—O—C(O)CH₃ or —O—C(O)CH₂CH₃; R⁴ is an optionally substituted N-linkedheterocycle moiety, wherein the N-linked heterocycle moiety is—N-pyrrolidine, —N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one,—N1-imidazole, —N1-4,5-dihydroimidazole, —N-morpholine, —N-piperidine,—N-indole, —N-indoline, —N-quinolidine or —N1-piperazine, optionallysubstituted at N4 with optionally substituted alkyl, aryl or heteroaryl;and R^(10A), R^(10B)R^(10C) or R^(10D) are —H, a halogen or —OR^(PR);

wherein R² is —OH or —OCH₃ when R^(10A), R^(10B)R^(10C) or R^(10D) is—H.

13B. The compound of embodiment 1B, wherein the compound has thestructure

wherein R¹ is —OH; R² is —H, —OH or —OCH₃; R³ is —H, —O—C(O)CH₃ or—O—C(O)CH₂CH₃; R⁴ is an optionally substituted N-linked heterocyclemoiety, wherein the N-linked heterocycle moiety is —N-pyrrolidine,—N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N-piperidine, —N-indole,—N-indoline, —N-quinolidine or —N1-piperazine, optionally substituted atN4 with optionally substituted alkyl, aryl or heteroaryl; and R^(10A),R^(10B), R^(10C) or R^(10D) independently are —H, a halogen or —OR^(PR),wherein R^(10A), R^(10B), R^(10C) or R^(10D) is a halogen or —OR^(PR)when R² and R³ are —H.

14B. The compound of embodiment 1B, wherein the compound has thestructure

wherein R¹ is —OH; R² is —H, —OH or —OCH₃; R³ is —H, a halogen,—O—C(O)CH₃ or —O—C(O)CH₂CH₃; R⁴ is an optionally substituted C-linkedheterocycle moiety, wherein the C-linked heterocycle moiety is2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl; and R^(10A),R^(10B), R^(10C) or R^(10D) is —H, a halogen or —OR^(PR) whereinR^(10A), R^(10B), R^(10C) or R^(10D) is a halogen or —OR^(PR) when R²and R³ are —H.

15B. The compound of embodiment 14B wherein R¹ and R² are —OH; R³ is —Hor —O—C(O)CH₃; R⁴ is 3-pyridyl; and R^(10A) or R^(10B) is —H, —OR^(PR)or —F.

16B. The compound of claim 1B, wherein the compound has the structure

or a salt thereof, wherein the dotted lines are optional double bonds;

wherein R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O,halogen, optionally substituted alkyl, ester or ether; R³ is —H, —OH,halogen, optionally substituted alkyl, ester or ether; R⁴ is optionallysubstituted heterocycle; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR) or —OR^(PR) and each R^(10A), R^(10B), R^(10C) andR^(10D) is independently in the α-configuration or the β-configurationand wherein R^(PR) independently are —H or a protecting group.

17B. The compound of embodiment 16B, wherein the compound has thestructure

18B. The compound of embodiment 16B, wherein the compound has thestructure

19B. The compound of embodiment 17B, wherein R¹ is —OH, ═O or—NH—C(O)CH₃; R² is —OH or —OCH₃; and R³ is —H, —OH, —O—C(O)CH₃ or—O—C(O)CH₂CH₃.

20B. The compound of embodiment 17B, wherein R⁴ is —N-pyrrolidine,—N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N1-pyridine, —N-piperidine or—N-piperazine.

21B. The compound of embodiment 17B, wherein R⁴ is 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl,6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

22B. The compound of embodiment 17B, wherein R⁴ is 1-aziridyl,azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, 2-isoindole, 2-isoindoline, 4-morpholine, 9-carbazole orβ-carboline.

23B. The compound of embodiment 16B, wherein the compound has thestructure

24B. The compound of embodiment 16B, wherein the compound is3β,16-dihydroxy-17-N-pyrrolidinylandrost-5,16-diene,3β,7β-dihydroxy-17-N-pyrrolidinylandrost-5,16-diene,3β-hydroxy-16α-fluoro-17β-N-pyrrolidinylandrost-1,16-diene.

25B. The compound of embodiment 16B, wherein the compound is17-(3-pyridyl)-androst-1,5,16 triene-3β-ol or17-(3-pyridyl)-16-fluoro-androst-1,5,16 triene-3β-ol,3β,7β-dihydroxy-17-(3-pyridyl)-5α-androst-16-ene or3β,7β-dihydroxy-17-(3-pyridyl)-androst-5,16-diene.

26B. The compound of embodiment 1B, wherein the compound has thestructure

or a salt thereof, wherein the dotted lines are optional double bonds;

wherein R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O,halogen, optionally substituted alkyl, ester or ether; R³ is —H, —OH,halogen, optionally substituted alkyl, ester or ether; R⁴ is optionallysubstituted heterocycle; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CHα-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR) or —OR^(PR) and each R^(10A), R^(10B), R^(10C) andR^(10D) is independently in the α-configuration or the β-configurationand wherein R^(PR) independently are —H or a protecting group.

27B. The compound of embodiment 26B, wherein the compound has thestructure

28B. The compound of embodiment 27B, wherein the compound has thestructure

29B. The compound of embodiment 26B, wherein the compound has thestructure

30B. The compound of embodiment 27B, wherein R¹ is —OH, ═O or—NH—C(O)CH₃; R² is —OH or —OCH₃; and R³ is —H, —OH, —O—C(O)CH₃ or—O—C(O)CH₂CH₃.

31B. The compound of embodiment 27B, wherein R⁴ is —N-pyrrolidine,—N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N1-pyridine, —N-piperidine or—N-piperazine.

32B. The compound of embodiment 27, wherein R⁴ is 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl,6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

33B. The compound of embodiment 27B, wherein R⁴ is 1-aziridyl,azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, 2-isoindole, 2-isoindoline, 4-morpholine, 9-carbazole orβ-carboline.

34B. A compound having a structure of

or a salt thereof; wherein the dotted lines are optional double bondsand —H at the 5-position (if present) is in the α- or β-configuration orif a double bond is present at the 1-2, 4-5 or 5-6 positions, thenR^(10A), R^(10B) or R^(10C) respectively are bonded to the ring to whichthey are linked by a single bond;

wherein R^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A) and R^(10D),R^(10B) and R^(10C), R^(10B) or R^(10D) and R^(10C) respectively are inthe α,α, α,β, β,α or β,β-configurations; one of R¹ is —H, an optionallysubstituted alkyl group, an optionally substituted alkenyl group or anoptionally substituted alkynyl group and the other R¹ is —OH, an ester,or an alkoxy group; R² and R³ independently are —H, —OH, an ester, anether or a halogen; one R⁴ is —OH, an ester or an alkoxy group and theother R⁴ is an optionally substituted C-linked heterocycle moiety,wherein the C-linked heterocycle moiety is 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl;R⁵ and R⁶ independently are —H or an optionally substituted alkyl group;R⁷, R⁸ and R⁹ independently are —C(R¹⁰)₂— or ═C(R¹⁰)—, wherein R¹⁰ areindependently selected; R¹⁰, R^(10A), R^(10B), R^(10C) and R^(10D)independently are —H, halogen, —SR^(PR) or —OR^(PR), wherein one ofR^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A) and R^(10D), R^(10B)and R^(10C), R^(10B) and R^(10D) or R^(10C) and R^(10D) are halogen,—SR^(PR) or —OR^(PR) and the other R^(10A), R^(10B), R^(10C) or R^(10D)are as defined; and R^(PR) independently are —H or a protecting group,wherein R^(PR) of —OR^(PR) defines an ester or an alkoxy group.

35B. The compound of embodiment 34B wherein R⁷, R⁸ and R⁹ independentlyare —CH₂—, —CF₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)-, wherein hydroxyl, the ester, the alkoxy group or thehalogen atom is present in the α-configuration and the alkoxy group is—OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl or —Br.

36B. The compound of embodiment 35B wherein the compound has a structure

37B. The compound of embodiment 36B wherein R⁵ and R⁶ independently are—H, —CH₃ or —CH₂OH; R⁷, R⁸ and R⁹ are —CH₂—; and R^(10A), R^(10B),R^(10C) and R^(10D) is a halogen or —OR^(PR).

38B. The compound of embodiment 34B wherein the compound has thestructure

39B. The compound of embodiment 38B, wherein R¹ is —OH; R² is —OH or—OCH₃; R³ is —H, a halogen, —O—C(O)CH₃ or —O—C(O)CH₂CH₃; one R⁴ is anoptionally substituted C-linked heterocycle moiety, wherein the C-linkedheterocycle is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyland the other R⁴ is —OH; and R^(10A), R^(10B), R^(10C) or R^(10D) is —H,—OR^(PR) or a halogen.

40B. The compound of embodiment 39B, wherein R¹ and R² are —OH; R³ is —Hor —O—C(O)CH₃; R⁴ is 3-pyridyl; and R^(10A), R^(10B), R^(10C) or R^(10D)is —OR^(PR) or —F.

41B. A compound having the structure

or a salt thereof, wherein the dotted lines are optional double bondsand —H at the 5-position (if present) is in the α- or β-configuration orif a double bond is present at the 1-2, 4-5 or 5-6 positions, thenR^(10A), R^(10B) or R^(10C) respectively are bonded to the ring to whichthey are linked by a single bond; R^(10A) and R^(10B), R^(10A) andR^(10C), R^(10A) and R^(10D), R^(10B) and R^(10C), R^(10B) or R^(10D)and R^(10C) respectively are in the α,α-, α,β-, β,α- orβ,β-configurations;

wherein one of R¹ is —H, an optionally substituted alkyl group, anoptionally substituted alkenyl group or an optionally substitutedalkynyl group and the other R¹ is —OH, an ester, or an alkoxy group; R²and R³ independently are —H, —OH, an ester, an alkoxy group or ahalogen; one R⁴ is —OH, an ester or an alkoxy group and the other R⁴ isan optionally substituted N-linked heterocycle; R⁵ and R⁶ independentlyare —H or an optionally substituted alkyl group; R⁷, R⁸ and R⁹independently are —C(R¹⁰)₂— or ═C(R¹⁰)—, wherein R¹⁰ are independentlyselected; R¹⁰, R^(10A), R^(10B), R^(10C) and R^(10D) independently are—H, halogen, —SR^(PR) or —OR^(PR); R^(PR) independently are —H or aprotecting group, wherein R^(PR) of —OR^(PR) defines an ester or analkoxy group;

wherein (1) one R² is as defined and the other R² is —OH, an ester or anether, or (2) one of R^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A)and R^(10D), R^(10B) and R^(10C), R^(10B) and R^(10D) or R^(10C) andR^(10D) are halogen, —SR^(PR) or —OR^(PR) and the other R^(10A),R^(10B), R^(10C) or R^(10D) are as defined.

42B. The compound of embodiment 41B wherein R⁷, R⁸ and R⁹ independentlyare —CH₂—, —CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)-, wherein hydroxyl, the ester, the alkoxy group or thehalogen atom is present in the α-configuration and the alkoxy group is—OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl or —Br.

43B. The compound of embodiment 42B, wherein the compound has thestructure

wherein R¹ is —OH, an ester or an alkoxy group; R² is —H, —OH, an esteror an alkoxy group; R³ is —H, a halogen, —OH, an ester or an alkoxygroup; one R⁴ is —H and other R⁴ is an optionally substituted N-linkedheterocycle moiety; R⁵ and R⁶ independently are —H, —CH₃ or —CH₂OH; andR⁷, R⁸ and R⁹ are —CH₂—;

wherein one of R^(10A) and R^(10B), R^(10A) and R^(10C), R^(10A) andR^(10D), R^(10B) and R^(10C), R^(10B) and R^(10D) or R^(10C) and R^(10D)are halogen or —OR^(PR) and the other R^(10A), R^(10B), R^(10C) orR^(10D) are as defined.

44B. The compound of embodiment 43B, wherein the compound has thestructure

wherein R¹ is —OH, an ester or an alkoxy group; R² is —H, —OH, an esteror an alkoxy group; R³ is —H a halogen, —OH, an ester or an alkoxygroup; one R⁴ is —H and the other R⁴ is an optionally substitutedN-linked heterocycle moiety; R^(10A) or R^(10B) is halogen or —OR^(PR).

45B. The compound of embodiment 41B, wherein the compound has thestructure

wherein one each of R¹ and R² are —H and the other R¹ and R²independently are —OH or an ester; one of R³ is —H and the other R³ is—OH, a halogen, an ester or an alkoxy group; one R⁴ is —H and the otherR⁴ is an optionally substituted N-linked heterocycle moiety; R⁵ is —CH₃,—CH₂CH₃ or —CH₂OH; R⁶ is —H, —CH₃ or —CH₂OH; and R⁷, R⁸ and R⁹ are—CH₂—.

46B. The compound of embodiment 45B, wherein the compound has thestructure

wherein one R⁴ is —OH and the other R⁴ is a N-linked heterocycle moietywherein the N-linked heterocycle moiety is —N-pyrrolidine,—N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N-piperidine, —N-indole,—N-indoline, —N-quinolidine or —N1-piperazine, optionally substituted atN4 with an optionally substituted alkyl, aryl or heteroaryl moiety.

47B. A compound having the structure

or a salt thereof, wherein the dotted lines are optional double bondsand —H at the 5-position (if present) is in the α- or β-configuration orif a double bond is present at the 1-2, 4-5 or 5-6 positions, thenR^(10A), R^(10B) or R^(10C) respectively are bonded to the ring to whichthey are linked by a single bond;

wherein one each of R¹, R² and R³ is —H and the other R¹ is —OH, theother R² and R³ independently are —H, —OH, a halogen, an ester or analkoxy group; one of R⁴ is —H or an optionally substituted alkyl groupthe other R⁴ is —NH₂, —N(R^(PR))₂, an optionally substituted aminemoiety or an optionally substituted amide group or both R⁴ together are═N—OH or ═NO-optionally substituted alkyl; R⁶ is —H or —CH₃; R⁷ is—CH(R¹⁰)₂—) or ═CH(R¹⁰)— and R⁸ and R⁹ independently are —C(R¹⁰)₂—,wherein R¹⁰ are independently selected; R¹⁰, R^(10A), R^(10B), R^(10C)and R^(10D) independently are —H, a halogen, —SR^(PR) or —OR^(PR);R^(PR) independently are —H or a protecting group; wherein theprotecting group defines —OR^(PR) as an ester or an alkoxy group;

wherein (1) R^(10A) in R^(10A) and R^(10B), R^(10A) and R^(10C) orR^(10A) and R^(10D) is a halogen, —OH, —SR^(PR) or —OR^(PR), and theother R^(10B), R^(10C) or R^(10D) are as defined, or (2) R^(10B) andR^(10C), R^(10B) and R^(10B) or R^(10C) and R^(10D) independently are ahalogen, —SR^(PR) or —OR^(PR), or (3) one R² and one R³ is as definedand the other R² and R³ independently are —OH, a halogen, an ester or analkoxy group; and wherein the optionally substituted alkyl groupsindependently are —CH₃, —CH₂CH₃, —CH₂OH, or —CH₂— (ester), the alkoxygroups independently are —OCH₃, —OC₂H₅ or —CH₃H₇, the estersindependently are a hydroxyl ester.

48B. The compound of embodiment 47B wherein the hydroxyl ester isacetate, enanthate, propionate, isopropionate, isobutyrate, butyrate,valerate, caproate, isocaproate, hexanoate, heptanoate, octanoate,nonanoate, decanoate, undecanoate, phenylacetate or benzoate.

49B. The compound of embodiment 47B wherein R¹⁰, R^(10A), R^(10B),R^(10C) and R^(10D) independently are —H, a halogen, —OH, an alkoxygroup or a hydroxyl ester, wherein the halogen atom is —F, —Cl or —Br,the alkoxy group is —OCH₃ or —OC₂H₅ and the hydroxyl ester is—O—C(O)—CH₃ or —O—C(O)—CH₂CH₃.

50B. The compound of embodiment 49B, wherein R¹⁰, R^(10A), R^(10B),R^(10C) and R^(10D) independently are —H, α-OH, or β-OH,

wherein (1) R^(10A) in R^(10A) and R^(10B), R^(10A) and R^(10C) orR^(10A) and R^(10D) is α-OH or β-OH and the other R^(10B), R^(10C) orR^(10D) is as defined, or (2) R^(10B) and R^(10C), R^(10B) and R^(10D)or R^(10C) and R^(10D) independently are α-OH or β-OH.

51B. The compound of embodiment 47B, wherein R⁷ is —C(R¹⁰)₂ or —C(R¹⁰)₂and R⁸ and R⁹ independently are —C(R¹⁰)₂— or ═C(R¹⁰)—, wherein one R¹⁰is —H, —OH, an ester, an alkoxy group or a halogen, in the α- orβ-configuration, and the other R¹⁰, if present, is —H.

52B. The compound of embodiment 51B, wherein R⁷, R⁸ and R⁹ independentlyare —CH₂—, —CF₂—, —CH(OH)—, —CH(R¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)-, wherein —OH, R¹⁰, the ester, the alkoxy group or thehalogen atom is present in the α-configuration; and wherein the halogenatom is —F, —Cl or —Br, the alkoxy group is —OCH₃, —OC₂H₅ or —OC₃H₇ andthe ester is —OC(O)—CH₃ or —OC(O)CH₂CH₃.

53B. The compound of embodiment 47B, wherein the other R² is —H, —OH oran alkoxy group, wherein the alkoxy group is —OCH₃, and the other R³ is—H, halogen, —OH or a hydroxyl ester, wherein the hyroxyl ester is—O—C(O)—CH₃ or —O—C(O)—CH₂CH₃; the other R⁴ is an optionally substitutedamine moiety or an optionally substituted amide group; R⁶ is —H or —CH₃;R⁷, R⁸ and R⁹ independently are —C(R¹⁰)₂, wherein R¹⁰ independently are—H, —OH or a halogen; R^(10A) is halogen or R^(10A) and R^(10B), R^(10A)and R^(10C) or R^(10A) and R^(10D), R^(10B) and R^(10C), R^(10B) andR^(10D) or R^(10C) and R^(10D) independently are —OH or a halogen; andwherein the halogens independently are —F, —Cl or —Br.

54B. The compound of embodiment 47B, wherein the compound has thestructure

wherein R¹ is —OH; R² is —OH or an alkoxy group; R³ is a halogen, —OH, ahydroxyl ester; and R⁴ is an optionally substituted amine moiety or═NOH.

55B. The compound of embodiment 47B, wherein R¹ and R² are —OH; R³ is—OH, ═O, a halogen or a hydroxyl ester, wherein the halogen atom is —For —Br and the hydroxyl ester is —O—C(O)—CH₃ or —O—C(O)—CH₂CH₃; and R⁴is an optionally substituted amine moiety, wherein the optionallysubstituted amine moiety is —NH₂, —NHCH₃, —N(CH₃)₂, —N⁺(CH₃)₃, —NH—C₂H₅or —NHOH, or an optionally substituted amide group, wherein theoptionally substituted amide group is —NH—C(O)CH₃.

56B. The compound of embodiment 55B, wherein the compound has thestructure

57B. The compound of embodiment 47B, wherein the compound is3β,7β-dihydroxy-6-chloro-16-oxo-17β-aminoandrost-5-ene,3β-hydroxy-6-chloro-16α-fluoro-17β-aminoandrost-5-ene,3β,7β-dihydroxy-6α-bromo-16-oxo-17β-aminoandrostane or3β-hydroxy-6α-bromo-16α-fluoro-17β-aminoandrostane.

58B. The compound of embodiment 47B, wherein the compound is3β,7β-dihydroxy-16-oxo-17β-aminoandrost-5-ene or3β,7β-dihydroxy-16α-fluoro-17β-aminoandrostane.

59B. A pharmaceutical formulation comprising one or more excipients anda compound according to claim 1B, 16B, 34B, 41B or 47B.

1C. A compound having the structure

or a salt thereof, wherein the dotted line is an optional double bond;

R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; R⁴ is optionallysubstituted heterocycle; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR) or —OR^(PR) and each R^(10A), R^(10B), R^(10C) andR^(10D) is independently in the α-configuration or the β-configurationand wherein R^(PR) independently are —H or a protecting group.

2C. The compound of embodiment 10 wherein the compound has the structure

3C. The compound of embodiment 10 wherein the compound has the structure

4C. The compound of embodiment 2C wherein R¹ is —OH, ═O or —NH—C(O)CH₃;R² is —OH or —OCH₃; and R³ is —H, —OH, —O—C(O)CH₃ or —O—C(O)CH₂CH₃.

5C. The compound of embodiment 10 wherein R⁴ is —N-pyrrolidine,—N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N1-pyridine, —N-piperidine or—N-piperazine.

6C. The compound of embodiment 1C wherein R⁴ is 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl,6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

7C. The compound of embodiment 10 wherein R⁴ is 1-aziridyl, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, 2-isoindole, 2-isoindoline, 4-morpholine, 9-carbazole orβ-carboline.

8. The compound of embodiment 1 wherein the compound has the structure

9C. A pharmaceutical formulation comprising one or more excipients and acompound according to embodiment 1C.

10C. A compound having the structure

or a salt thereof, wherein the dotted line is an optional double bond;

R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; R⁴ is optionallysubstituted heterocycle; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR) or —OR^(PR) and each R^(10A), R^(10B), R^(10C) andR^(10D) is independently in the α-configuration or the β-configurationand wherein R^(PR) independently are —H or a protecting group.

11C. The compound of embodiment 10C wherein the compound has thestructure

12C. The compound of embodiment 11C wherein the compound has thestructure

13C. The compound of embodiment 10C wherein the compound has thestructure

14C. The compound of embodiment 110 wherein R¹ is —OH, ═O or—NH—C(O)CH₃; R² is —OH or —OCH₃; and R³ is —H, —OH, —O—C(O)CH₃ or—O—C(O)CH₂CH₃.

15C. The compound of embodiment 10 wherein R⁴ is —N-pyrrolidine,—N1-pyrazolone, —N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N1-pyridine, —N-piperidine or—N-piperazine.

16C. The compound of embodiment 10 wherein R⁴ is 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl,6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

17C. The compound of embodiment 10 wherein R⁴ is 1-aziridyl, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, 2-isoindole, 2-isoindoline, 4-morpholine, 9-carbazole orβ-carboline.

18C. A pharmaceutical formulation comprising one or more excipients anda compound according to embodiment 10C.

19C. A compound having the structure

or a salt thereof, wherein the dotted lines are optional double bonds;

R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; R⁴ is —OH, ester, ether,—NH₂, —NH—C(O)CH₃, —NH—CH₃, —N(CH₃)₂, —NHOH or optionally substitutedheterocycle; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅, —C₃H₇,optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—C(halogen)₂-, —CH(α-optionally substituted alkyl), —CH(β-optionallysubstituted alkyl), —CH(α-OH), —CH(β-OH) or —C(optionally substitutedalkyl)₂-; and R⁹ is —CH(α-OH), —CH(β-OH) or —C(optionally substitutedalkyl)₂-.

20C. The compound of embodiment 19C wherein the compound has thestructure

21C. A pharmaceutical formulation comprising one or more excipients anda compound according to embodiment 19.

22C. A compound having the structure

or a salt thereof, wherein the dotted lines are optional double bonds;

R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; one R⁴ is —OH, ester,ether, —NH₂, —NH—C(O)CH₃, —NH—CH₃, —N(CH₃)₂, —NHOH or optionallysubstituted heterocycle; the other R⁴ is —H, optionally substitutedalkyl, halogen, —SH or —OH; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR) or —OR^(PR) and each R^(10A), R^(10B), R^(10C) andR^(10D) is independently in the α-configuration or the β-configuration,wherein R^(PR) independently are —H or a protecting group and whereinone or two of R^(10A), R^(10B), R^(10C) and R^(10D) are not —H.

23C. The compound of embodiment 22C wherein the compound has thestructure

24C. A compound having the structure

or a salt thereof, wherein the dotted lines are optional double bonds;

R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —H, —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; one R⁴ is —OH, ester,ether, —NH₂, —NH—C(O)CH₃, —NH—CH₃, —N(CH₃)₂, —NHOH or optionallysubstituted heterocycle; the other R⁴ is —H, optionally substitutedalkyl, halogen, —SH or —OH; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CF(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR), —OR^(PR), α-OH, β-OH or ═O and each R^(10A), R^(10B),R^(10C) and R^(10D) is independently in the α-configuration or theβ-configuration, wherein R^(PR) independently are —H or a protectinggroup and wherein R^(10A) and R^(10C), R^(10A) and R^(10C) or R^(10C)and R^(10D) are not —H.

25C. The compound of embodiment 24C wherein the compound has thestructure

wherein R^(10A) and R^(10C) or R^(10C) and R^(10D) independently areα-OH, β-OH or ═O.

26. A pharmaceutical formulation comprising one or more excipients and acompound according to claim 24.

1. A method to prevent, treat, ameliorate or slow the progression ofcystic fibrosis, sickle cell disease, neutropenia or thrombocytpoenia ina subject, or to treat a symptom of the neutropenia or thrombocytopenia,comprising administering to a subject, or delivering to the subject'stissues, an effective amount of a formula 1 compound having thestructure 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14

or a metabolic precursor or a metabolite thereof, wherein R¹⁰ moietiesat the 5 (if present), 8, 9 and 14 positions respectively are in theα,α,α,α, α,α,α,β, α,α,β,α, α,α,α,α, β,α,α,α, α,α,β,β, α,β,β,β, β,α,α,β,β,α,β,α, β,β,α,α, α,β,β,α, α,α,β,β, β,α,β,β, β,β,α,β, β,β,β,α orβ,β,β,βconfigurations, wherein R^(10A), R^(10B), R^(10C), R^(10D) andR^(10E) respectively are in the α,α, α,β, β,α or β,β configurations,

wherein, each R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) independently are —H, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, an ester, a thioester, a thionoester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate, a carbamate, ahalogen, an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety, an optionally substituted heteroarylmoiety, an optionally substituted heterocycle, an optionally substitutedmonosaccharide, an optionally substituted oligosaccharide, a nucleoside,a nucleotide, an oligonucleotide, a polymer, or

one or more of R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) are ═O, ═S, ═N—OH, ═CH₂, ═CH—CH₃, or anindependently selected spiro ring and the hydrogen atom or the secondvariable group that is bonded to the same carbon atom is absent, or oneor more of two adjacent R¹-R⁶, R¹⁰, R^(10A), R^(10B), R^(10C), R^(10D)and R^(10E) comprise an independently selected epoxide, acetal, athioacetal, ketal or thioketal;

R⁷ is —C(R¹⁰)₂—, —C(R¹⁰)₂₋₀(R¹⁰)_(2l —, —C(R) ¹⁰)₂₋₀(R¹⁰)₂₋₀(R¹⁰)₂,—C(R¹⁰)₂—O—C(R¹⁰)₂—, —C(R¹⁰)₂—S—C(R¹⁰)₂—, —C(R¹⁰)₂—NR^(PR)—C(R¹⁰)₂—,—O—, —O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—; R⁸and R⁹ independently are —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —O—, —O—C(R¹⁰)₂—,—S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—, or one or both of R⁸or R⁹ independently are absent, leaving a 5-membered ring; R¹³independently is C₁₋₆ alkyl; and R^(PR) independently is —H or aprotecting group;

optionally provided that (1) one or two of R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) are not hydrogen or (2) one R⁴ is —NH₂, anoptionally substituted amine, —N(R^(PR))², ═NOH, ═NO-optionallysubstituted alkyl, an amide or an N-linked amino acid. In theseembodiments, the subject may have or be subject to developing the listedcondition and the subject can be a human or a primate.

2. The method of embodiment 1 wherein one each of R¹, R², R³ and R⁴ are—H, and, when no double bond links the second R¹, R², R³ and R⁴ to thering to which it is bonded and no double bond is present at the 16-17position, then the second R¹, R², R³ and R⁴ respectively are in theα,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β, β,α,α,β,β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,α or β,β,β,βconfigurations and the second R¹, R², R³ and R⁴ are optionallyindependently selected from —H, —F, —Cl, —Br, —I, —OH, —SH, —NH₂, —COOH,—CH₃, —C₂H₅, —C(CH₃)₃, —OCH₃, —OC₂H₅, —CF₃, —CH₂OH, —C(O)CH₃,—C(O)CH₂OH, —C(O)CH₂F, —C(O)CH₂Cl, —C(O)CH₂Br, —C(O)CH₂I, —C(O)CF₃,—C₂F₅, ═O, ═CH₂, ═CHCH₃, amino acid, carbamate, carbonate, optionallysubstituted C1-C20 alkyl, optionally substituted C1-C20 ether,optionally substituted C1-C20 ester, optionally substituted C1-C20thioether, optionally substituted C1-C20 thioester, optionallysubstituted monosaccharide, optionally substituted disaccharide,optionally substituted oligosaccharide.

3. The method of embodiment 1 or 2 wherein (a) R^(10A) is bonded to thering to which it is attached by a single bond and a double bond ispresent at (i) the 1-2 position, or (ii) the 1-2 and 16-17 positions; or(b) R^(10B) is bonded to the ring to which it is attached by a singlebond and a double bond is present at the 4-5 position; or (c) R^(10C) isbonded to the ring to which it is attached by a single bond and a doublebond is present at the 5-6 position; or (d) R^(10A) and R^(10B) arebonded to the rings to which they are attached by a single bond and adouble bond is present at (i) the 1-2 and 4-5 positions, or (ii) the1-2, 4-5 and 16-17 positions; and (e) R^(10A) and R^(10C) are bonded tothe rings to which they are attached by a single bond and a double bondis present at (i) the 1-2 and 5-6 positions, or (ii) the 1-2, 5-6 and16-17 positions; or (f) no double bond is present.

4. The method of embodiment 1, 2 or 3 wherein the compounds of structure5, 6, 7, 8, 9, 10, 11 and 12 have the structure

provided that if a double bond is present at the 1-2, 4-5 or 5-6positions, then R^(10A), R^(10B) or R^(10C) respectively are bonded tothe ring to which they are linked by a single bond and wherein, when R¹,R², R³ and R⁴ are single bonded, one is in the α-configuration and theother R¹, R², R³ and R⁴ is in the β-configuration.

5. The method of embodiment 1, 2, 3 or 4 wherein (1) R⁵ and R⁶respectively are in the α,α, α,β, β,α or β,β configuration and R⁵ and R⁶are optionally both —CH₃ or are optionally selected from —CH₃ and —CH₂OHor (2) R⁵ and R⁶ are both in the β-configuration and R⁵ and R⁶ areoptionally both —CH₃ or are optionally —CH₃ and —CH₂OH.

6. The method of embodiment 1, 2, 3, 4 or 5 wherein R⁵ and R⁶ areoptionally both in the β-configuration and are optionally independentlyselected from —H, —F, —Br, —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂CH₂OH, —CH(O),—CH₂OH, —CH₂-ester, —CH₂-ether, —CH₂-amino acid, —CH₂-carbamate,—CH₂OR^(PR), —CHS, —CH₂SH, —CH₂SR^(PR), —CH₂-thioester, —CH₂-thioether,—CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂CC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, and an ester wherein nis 0, 1, 2, 3 or 4 and R^(PR) are independently selected protectinggroups for atoms to which they are bonded.

7. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein one each of R¹,R², R³ and R⁴ are —H and wherein (i) no double bond is present at the16-17 position, the second R¹, R², R³ and R⁴ respectively are bonded tothe ring to which they are attached by a single bond in the β,β,α,βconfigurations (i.e., R¹ is in the β-configuration, R² is in theβ-configuration, R³ is in the α-configuration and R⁴ is in theβ-configuration when no double bond is present at 16-17), or (ii) adouble bond is present at the 16-17 position and R¹ and R² respectivelyare in the β,β configurations (i.e., R¹ is in the β-configuration and R²is in the β-configuration when a double bond is present at 16-17).

8. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the β,β,β,βconfigurations or (ii) one each of R¹, R² and R³ are —H, no double bondis present at the 16-17 position, the second R¹, R² and R³ respectivelyare bonded to the ring to which they are attached by a single bond inthe β,β,β, β,β,α, β,α,β, α,β,β, β,α,α, α,β,α, α,α,β orα,α,αconfigurations and both R⁴ together are bonded to the ring by adouble bond (i.e., both R⁴ together are a double bonded moiety describedherein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

9. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the β,β,β,αconfigurations or (ii) one each of R¹, R² and R⁴ are —H, no double bondis present at the 16-17 position, the second R¹, R² and R⁴ respectivelyare bonded to the ring to which they are attached by a single bond inthe β,β,β, β,β,α, β,α,β, α,β,β, β,α,α, α,β,α, α,α,β or α,α,αconfigurations and both R³ together are bonded to the ring by a doublebond (i.e., both R³ together are a double bonded moiety described hereinsuch as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

10. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein no double bondis present at the 16-17 position, one each of R¹, R², R³ and R⁴ are —Hand the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the β,β,α,α configurations.

11. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the β,α,β,β configurations(i.e., R¹ is in the β-configuration, R² is in the α-configuration, R³ isin the β-configuration and R⁴ is in the β-configuration when no doublebond is present at 16-17), or (ii) a double bond is present at the 16-17position and R¹ and R² respectively are in the β,αconfigurations (i.e.,R¹ is in the β-configuration and R² is in the α-configuration when adouble bond is present at 16-17).

12. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the β,α,β,αconfigurations or (ii) one each of R¹, R³ and R⁴ are —H, no double bondis present at the 16-17 position, the second R¹, R³ and R⁴ respectivelyare bonded to the ring to which they are attached by a single bond inthe β,β,β, β,β,α, β,α,β, α,β,β, β,α,α, α,β,α, α,α,β or α,α,αconfigurations and both R² together are bonded to the ring by a doublebond (i.e., both R² together are a double bonded moiety described hereinsuch as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

13. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the β,α,α,βconfigurations or (ii) one each of R², R³ and R⁴ are —H, no double bondis present at the 16-17 position, the second R², R³ and R⁴ respectivelyare bonded to the ring to which they are attached by a single bond inthe β,β,β, β,β,α, β,α,β, α,β,β, β,α,α, α,β,α, α,α,β or α,α,αconfigurations and both R¹ together are bonded to the ring by a doublebond (i.e., both R¹ together are a double bonded moiety described hereinsuch as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

14. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein no double bondis present at the 16-17 position, one each of R¹, R², R³ and R⁴ are —H,and the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the β,α,α,α configurations.

15. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the α,β,β,β configurations(i.e., R¹ is in the α-configuration, R² is in the β-configuration, R³ isin the β-configuration and R⁴ is in the β-configuration when no doublebond is present at 16-17), or (ii) a double bond is present at the 16-17position and R¹ and R² respectively are in the α,β configurations (i.e.,R¹ is in the α-configuration and R² is in the β-configuration when adouble bond is present at 16-17).

16. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,β,α,βconfigurations or (ii) one each of R¹ and R³ are —H, no double bond ispresent at the 16-17 position, the second R¹ and R³ respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R² together and both R⁴together are bonded to the ring by a double bond (i.e., both R² togetherand both R⁴ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

17. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,β,β,αconfigurations or (ii) one each of R² and R³ are —H, no double bond ispresent at the 16-17 position, the second R² and R³ respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R¹ together and both R⁴together are bonded to the ring by a double bond (i.e., both R¹ togetherand both R⁴ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

18. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein no double bondis present at the 16-17 position, one each of R¹, R², R³ and R⁴ are —H,and the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the α,β,α,α configurations.

19. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the α,α,β,β configurations(i.e., R¹ is in the α-configuration, R² is in the α-configuration, R³ isin the β-configuration and R⁴ is in the β-configuration when no doublebond is present at 16-17), or (ii) a double bond is present at the 16-17position and R¹ and R² respectively are in the α,α configurations (i.e.,R¹ and R² are both in the α-configuration when a double bond is presentat 16-17).

20. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,α,α,βconfigurations or (ii) one each of R¹ and R⁴ are —H, no double bond ispresent at the 16-17 position, the second R¹ and R⁴ respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R² together and both R³together are bonded to the ring by a double bond (i.e., both R² togetherand both R³ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

21. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,α,β,αconfigurations or (ii) one each of R² and R⁴ are —H, no double bond ispresent at the 16-17 position, the second R² and R⁴ respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R¹ together and both R³together are bonded to the ring by a double bond (i.e., both R¹ togetherand both R³ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

22. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,α,α,αconfigurations or (ii) one each of R¹ and R² are —H, no double bond ispresent at the 16-17 position, the second R¹ and R² respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R³ together and both R⁴together are bonded to the ring by a double bond (i.e., both R³ togetherand both R⁴ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃) or (iii) one each ofR³ and R⁴ are —H, no double bond is present at the 16-17 position, thesecond R³ and R⁴ respectively are bonded to the ring to which they areattached by a single bond in the β,β, β,α, α,β or α,α configurations andboth R¹ together and both R² together are bonded to the ring by a doublebond (i.e., both R¹ together and both R² together are an independentlyselected double bonded moiety described herein such as ═O, ═NOH, ═CH₂ or═CH—CH₃).

23. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,β,α,α configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the β,α,α configurations.

24. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the β,β,α,α configurations.

25. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,β,α,β configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the β,α,β configurations.

26. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the β,β,α,β configurations.

27. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,β,β,α configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the β,β,α configurations.

28. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the β,β,β,α configurations.

29. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,α,α,α configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the α,α,α configurations.

30. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the β,α,α,α configurations.

31. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,α,α,β, α,α,α,α, α,α,β,β, β,α,α,β,β,α,β,α, α,β,β,β, β,α,β,β, or β,β,β,β configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the α,α,β, α,β,α, α,β,β or β,β,βconfigurations.

32. The method of any of embodiments 1 through 31 wherein R¹⁰ at the 5,8, 9 and 14-positions are independently selected from —H, —F, —Cl, —Br,—I, —OH, —OR^(PR), —SH, —NH₂, —COOH, —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂C₁, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate, an ester, optionally substituted C1-C20 alkyl optionallyselected from —CH₃, —C₂H₅ and —C₃H₇, optionally substituted C1-C20 etheroptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇, optionallysubstituted C1-C20 ester optionally selected from acetoxy andpropionoxy, optionally substituted aryl optionally selected from—O-phenyl, —O-(alkoxy)₁₋₃-phenyl where each alkoxy is optionallyindependently selected (e.g., methoxy or ethoxy) and —O-(halo)₁₋₃-phenylwhere each halogen is optionally independently selected (e.g., —F or—Cl).

33. The method of any of embodiments 1 through 31 wherein R¹⁰ at the 5,8, 9 and 14-positions respectively are (1) —H, —H, —H, —H, (2) —H, —H,halogen (—F, —Cl, —Br or —I), —H, (3) —H, —H, —H, —OH, (4) —H, —H,halogen (—F, —Cl, —Br or —I), —OH, (5)—optionally substituted alkyl(e.g., —CH₃, —CH₂OH, —CH₂O-ester, —C₂H₅), —H, —H, —H, (6)—optionallysubstituted alkyl (e.g., —CH₃, —CH₂OH, —CH₂O-ester, —C₂H₅), —H, halogen(—F, —Cl, —Br or —I), —H, (7)—optionally substituted alkyl (e.g., —CH₃,—CH₂OH, —CH₂O-ester, —C₂H₅), —H, —H, —OH, (8)—acyl (e.g.,—C(O)—(CH₂)₀₋₂—CH₃), —H, —H, —H, (9)—ester (e.g., acetoxy orpropionoxy), —H, —H, —H, (10)—ether (e.g., —O—(CH₂)₀₋₂—CH₃), —H, —H, —H,(11)—ester (e.g., acetoxy, propionoxy, —O—C(O)—(CH₂)₁₋₆—H), —H, halogen(e.g., —F, —Cl, —Br), —H, (12)—ester (e.g., acetoxy or propionoxy), —H,—H, —OH, (13) —H, —H, —H, -acyl (e.g., —C(O)—(CH₂)₀₋₂—CH₃), (14) —H, —H,—H, -ester (e.g., acetoxy or propionoxy), or (15) —H, —H, —H, -ether(e.g., —O—(CH₂)₀₋₂—CH₃, —OCH₃, —OC₂H₅, —OCH₂OH, —OCH₂F, —OCH₂Br,—OCH₂COOH, —OCH₂NH₂, —OCH₂CH₂OH, —OCH₂CH₂F, —OCH₂CH₂Br, —OCH₂CH₂COOH or—OCH₂CH₂NH₂).

34. The method of any of embodiments 1 through 33 wherein R¹⁰ at the5-position is in the α-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CH(O), —CH(S), —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate and an ester.

35. The method of any of embodiments 1 through 33 wherein R¹⁰ at the5-position is in the β-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate and an ester.

36. The method of any of embodiments 1 through 35 wherein R¹⁰ at the8-position is in the α-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate and an ester.

37. The method of any of embodiments 1 through 35 wherein R¹⁰ at the8-position is in the β-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate and an ester.

38. The method of any of embodiments 1 through 37 wherein R¹⁰ at the9-position is in the α-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate and an ester.

39. The method of any of embodiments 1 through 37 wherein R¹⁰ at the9-position is in the β-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate and an ester.

40. The method of any of embodiments 1 through 39 wherein R¹⁰ at the14-position is in the α-configuration and is optionally selected from—H, —F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate and an ester.

41. The method of any of embodiments 1 through 39 wherein R¹⁰ at the14-position is in the β-configuration and is optionally selected from—H, —F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)n-CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)n-C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)n-NHR^(PR), a monosaccharide, an amino acid, a carbonate,a carbamate and an ester.

42. The method of any of embodiments 1 through 41 wherein R⁷ is —CH₂—,—CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)- where thehydroxyl, ester or alkoxy group or the halogen atom is present in theα-configuration and the alkoxy group is optionally selected from —OCH₃,—OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl, —Br or —I.

43. The method of any of embodiments 1 through 41 wherein R⁷ is (i)—CHOH—, —CF₂—, —C(R¹⁰)₂—, —CH(βR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)-, wherein the hydroxyl, ester or alkoxy group or thehalogen atom is present in the β-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I or (ii) wherein R⁷ is —C(βCH₃)(αOH)—,—C(αCH₃)(βOH)—, —C(βCH₃)(αF)—, —C(αCH₃)(βF)—, —CF₂—, —C(βCH₃)(αCl)—,—C(αCH₃)(βCl)—, —CCl₂—, —C(βCH₃)(αBr)—, —C(αCH₃)(βBr)—, —CBr₂—,—C(βCH₃)(αI)—, —C(αCH₃)(βI)—, or —CI₂—.

44. The method of any of embodiments 1 through 41 wherein R⁷ is —C(O)—,—C(═CHCH₃)—, —C(═CH₂)—, —C(═CH—(CH₂)_(n)—CH₃)—,—C(═CH—(CH₂)_(n)—CH₂OH)—, —C(═CH—(CH₂)_(n)—CH₂F)—,—C(═CH—(CH₂)_(n)—CH₂Cl)—, —C(═CH—(CH₂)_(n)—CH₂Br)—,—C(═CH—(CH₂)_(n)—CH₂I)—, —C(═NOH)—, —C(═NO—(CH₂)_(n)—CH₃), wherein n is0, 1, 2, 3 or 4.

45. The method of any of embodiments 1 through 44 wherein R⁸ is —CH₂—,—CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)- where thehydroxyl, ester or alkoxy group or the halogen atom is present in theα-configuration and the alkoxy group is optionally selected from —OCH₃,—OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl, —Br or —I.

46. The method of any of embodiments 1 through 44 wherein R⁸ is (i)—CHOH—, —CF₂—, —C(R¹⁰)₂—, —CH(βR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)-, wherein the hydroxyl, ester or alkoxy group or thehalogen atom is present in the β-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I or (ii) wherein R⁸—O(βCH₃)(αOH)—, —O(αCH₃)(βOH)—,—O(βCH₃)(αF)—, —C(αCH₃)(βF)—, —CF₂—, —C(βCH₃)(αCl)—, —C(αCH₃)(βCl)—,—CCl₂—, —C(βCH₃)(αBr)—, —C(αCH₃)(βBr)—, —CBr₂—, —C(βCH₃)(βI)—,—C(αCH₃)(βI)—, or —CI₂—.

47. The method of any of embodiments 1 through 44 wherein R⁸ is —C(O)—,—CH₂—, —C(═CHCH₃)—, —(═CH₂)—, —C(═CH—(CH₂)_(n)—CH₃)—,—C(═CH—(CH₂)_(n)—CH₂OH)—, —C(═CH—(CH₂)_(n)—CH₂F)—,—C(═CH—(CH₂)_(n)—CH₂Cl)—, —C(═CH—(CH₂)_(n)—CH₂Br)—,—C(═CH—(CH₂)_(n)—CH₂I)—, —C(═NOH)—, —C(═NO—(CH₂)_(n)—CH₃), wherein n is0, 1, 2, 3 or 4.

48. The method of any of embodiments 1 through 47 wherein R⁹ is —CH₂—,—CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)-, whereinthe hydroxyl, ester or alkoxy group or the halogen atom is present inthe α-configuration and the alkoxy group is optionally selected from—OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl, —Br or —I.

49. The method of any of embodiments 1 through 47 wherein R⁹ is (i)—CHOH—, —CF₂—, —C(R¹⁰)₂—, —CH(βR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)-, wherein the hydroxy, ester or alkoxy group or the halogenatom is present in the β-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I, or (ii) wherein R⁹ is —C(βCH₃)(αOH)—,—C(αCH₃)(βOH)—, —C(βCH₃)(αF)—, —C(αCH₃)(βF)—, —CF₂—, —C(βCH₃)(αCl)—,—C(αCH₃)(βCl)—, —CCl₂—, —C(βCH₃)(αBr)—, —C(αCH₃)(βBr)—, —CBr₂—,—C(βCH₃)(αI)—, —C(αCH₃)(βI)—, or —CI₂—.

50. The method of any of embodiments 1 through 47 wherein R⁹ is —C(O)—,—CH₂—, —C(═CHCH₃)—, —C(═CH₂)—, —C(═CH—(CH₂)_(n)—CH₃)—,—C(═CH—(CH₂)_(n)—CH₂OH)—, —C(═CH—(CH₂)_(n)—CH₂F)—,—C(═CH—(CH₂)_(n)—CH₂Cl)—, —C(═CH—(CH₂)_(n)—CH₂Br)—,—C(═CH—(CH₂)_(n)—CH₂I)—, —C(═NOH)—, —C(═NO—(CH₂)_(n)—CH₃), wherein n is0, 1, 2, 3 or 4.

51. The method of any of embodiments 1 through 50 wherein the subjecthas, or is subject or susceptible to developing, neutropenia.

52. The method of any of embodiments 1-50 wherein the subject is amammal.

53. The method of embodiment 52 wherein the mammal is a human.

54. The method of any preceeding embodiment wherein R⁷ is —CH₂—,—C(α-OH, β-H)—, —C(β-OH, α-H)— or —C(O)—.

55. The method of any preceeding embodiment wherein R⁸ is —CH₂—,—C(α-OH, β-H)—, —C(β-OH, α-H)—, —C(α-OH, β-F)—, —C(β-OH, α-F)—, —C(α-F,(β-H)—, —C(β-F, α-H)— or —C(O).

56. The method of any preceeding embodiment wherein R⁹ is —CH₂—,—C(α-OH, β-H)—, —C(β-OH, α-H)— or —C(O)—.

57. The method of any preceeding embodiment wherein R^(10A) is —H, α-OH,β-OH or ═O.

58. The method of any preceeding embodiment wherein R^(10B) is —H, α-OH,β-OH or ═O.

59. The method of any preceeding embodiment wherein R^(10C) is —H, α-OH,β-OH or ═O.

60. The method of any preceeding embodiment wherein R^(10D) is —H, α-OH,β-OH or ═O.

61. The method of any preceeding embodiment wherein R^(10E) is —H, α-OH,β-OH or ═O.

62. The method of any preceeding embodiment wherein R⁴ are (α-OH, β-H),(β-OH, α-H), (α-C(O)CH₃, β-H), (β-C(O)CH₃, α-H), (α-OH, β-F), (β-OH,α-F), (α-H, β-F), (β-H, α-F), (α-NH₂, β-H), (β-NH₂, α-H), ═O, ═CH₂ or═CH—CH₃.

63. The method of any preceeding embodiment wherein R¹ are (H, H),(α-OH, β-H), (β-OH, α-H) or ═O.

64. The method of any preceeding embodiment wherein R² are (H, H),(α-OH, β-H), (β-OH, α-H) or ═O.

65. The method of any preceeding embodiment wherein R³ are (H, H),(α-OH, β-H), (β-OH, α-H), (α-H, β-F), (β-H, α-F) or ═O.

66. The method of any of embodiments 1-65 wherein the formula 1 compoundis 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-fluoro-3β-hydroxy-5α-androstan-17-one,16α-chloro-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-fluoro-3β-hydroxy-5α-androstan-17-one,16β-chloro-3β-hydroxy-5α-androstan-17-one,16α,3β-dihydroxy-5α-androstan-17-one,16β,3α-dihydroxy-5α-androstan-17-one,16α,3α-dihydroxy-5α-androstan-17-one,16β,3α-dihydroxy-5α-androstan-17-one,16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate,3α-hydroxy-16α-fluoroandrostane-17-one,3β-hydroxy-16α-fluoroandrostane-17-one,17α-hydroxy-16α-fluoroandrostane-3-one,17β-hydroxy-16α-fluoroandrostane-3-one,17α-hydroxy-16α-fluoroandrostane-4-one,17β-hydroxy-16α-fluoroandrostane-4-one,17α-hydroxy-16α-fluoroandrostane-6-one,17β-hydroxy-16α-fluoroandrostane-6-one,17α-hydroxy-16α-fluoroandrostane-7-one,17β-hydroxy-16α-fluoroandrostane-7-one,17α-hydroxy-16α-fluoroandrostane-11-one,17β-hydroxy-16α-fluoroandrostane-11-one, 16α-fluoroandrost-5-ene-17-one,7α-hydroxy-16α-fluoroandrost-5-ene-17-one,7β-hydroxy-16α-fluoroandrost-5-ene-17-one,4α-hydroxy-16α-fluoroandrost-5-ene-17-one,3α-hydroxy-16α-fluoroandrost-5-ene-17-one,3β-hydroxy-16α-fluoroandrost-5-ene-17-one,4β-hydroxy-16α-fluoroandrost-5-ene-17-one,6α-hydroxy-16α-fluoroandrost-5-ene-17-one,6β-hydroxy-16α-fluoroandrost-5-ene-17-one,11α-hydroxy-16α-fluoroandrost-5-ene-17-one,11β-hydroxy-16α-fluoroandrost-5-ene-17-one,4α,17β-dihydroxy-16α-fluoroandrost-5-ene,4β,17β-dihydroxy-16α-fluoroandrost-5-ene,6α,17β-dihydroxy-16α-fluoroandrost-5-ene,6β,17β-dihydroxy-16α-fluoroandrost-5-ene,11α,17β-dihydroxy-16α-fluoroandrost-5-ene,11β,17β-dihydroxy-16α-fluoroandrost-5-ene,4α,17α-dihydroxy-16α-fluoroandrost-5-ene,4β,17α-dihydroxy-16α-fluoroandrost-5-ene,6α,17α-dihydroxy-16α-fluoroandrost-5-ene,6β,17α-dihydroxy-16α-fluoroandrost-5-ene,11α,17α-dihydroxy-16α-fluoroandrost-5-ene,11β,17α-dihydroxy-16α-fluoroandrost-5-ene,7α,17β-dihydroxy-16α-fluoroandrost-5-ene,7β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17α-dihydroxy-16α-fluoroandrost-5-ene,3β,17α-dihydroxy-16α-fluoroandrost-5-ene,1α,17β-dihydroxy-16α-fluoroandrost-5-ene,1β,17β-dihydroxy-16α-fluoroandrost-5-ene,2α,17β-dihydroxy-16α-fluoroandrost-5-ene,2β,17β-dihydroxy-16α-fluoroandrost-5-ene,12α,17β-dihydroxy-16α-fluoroandrost-5-ene,12β,17β-dihydroxy-16α-fluoroandrost-5-ene,1α,17α-dihydroxy-16α-fluoroandrost-5-ene,1β,17α-dihydroxy-16α-fluoroandrost-5-ene,2α,17α-dihydroxy-16α-fluoroandrost-5-ene,2β,17α-dihydroxy-16α-fluoroandrost-5-ene,12α,17α-dihydroxy-16α-fluoroandrost-5-ene,12β,17α-dihydroxy-16α-fluoroandrost-5-ene,15α,17β-dihydroxy-16α-fluoroandrost-5-ene,15β,17β-dihydroxy-16α-fluoroandrost-5-ene,17β,18-dihydroxy-16α-fluoroandrost-5-ene,17β,19-dihydroxy-16α-fluoroandrost-5-ene,15α,17α-dihydroxy-16α-fluoroandrost-5-ene,15β,17α-dihydroxy-16α-fluoroandrost-5-ene,17α,18-dihydroxy-16α-fluoroandrost-5-ene,17α,19-dihydroxy-16α-fluoroandrost-5-ene,16α-fluoroandrost-4-ene-17-one,7α-hydroxy-16α-fluoroandrost-4-ene-17-one,7β-hydroxy-16α-fluoroandrost-4-ene-17-one,3α-hydroxy-16α-fluoroandrost-4-ene-17-one,3β-hydroxy-16α-fluoroandrost-4-ene-17-one,4α-hydroxy-16α-fluoroandrost-4-ene-17-one,4β-hydroxy-16α-fluoroandrost-4-ene-17-one,6α-hydroxy-16α-fluoroandrost-4-ene-17-one,6β-hydroxy-16α-fluoroandrost-4-ene-17-one,11α-hydroxy-16α-fluoroandrost-4-ene-17-one,11β-hydroxy-16α-fluoroandrost-4-ene-17-one,4α,17β-dihydroxy-16α-fluoroandrost-4-ene,4β,17β-dihydroxy-16α-fluoroandrost-4-ene,6α,17β-dihydroxy-16α-fluoroandrost-4-ene,6β,17β-dihydroxy-16α-fluoroandrost-4-ene,11α,17β-dihydroxy-16α-fluoroandrost-4-ene,11β,17β-dihydroxy-16α-fluoroandrost-4-ene,4α,17α-dihydroxy-16α-fluoroandrost-4-ene,4β,17α-dihydroxy-16α-fluoroandrost-4-ene,6α,17α-dihydroxy-16α-fluoroandrost-4-ene,6β,17α-dihydroxy-16α-fluoroandrost-4-ene,11α,17α-dihydroxy-16α-fluoroandrost-4-ene,11β,17α-dihydroxy-16α-fluoroandrost-4-ene,7α,17β-dihydroxy-16α-fluoroandrost-4-ene,7β,17β-dihydroxy-16α-fluoroandrost-4-ene,3α,17β-dihydroxy-16α-fluoroandrost-4-ene,3β,17β-dihydroxy-16α-fluoroandrost-4-ene,3α,17α-dihydroxy-16α-fluoroandrost-4-ene,3β,17α-dihydroxy-16α-fluoroandrost-4-ene,1α,17β-dihydroxy-16α-fluoroandrost-4-ene,1β,17β-dihydroxy-16α-fluoroandrost-4-ene,2α,17β-dihydroxy-16α-fluoroandrost-4-ene,2β,17β-dihydroxy-16α-fluoroandrost-4-ene,12α,17β-dihydroxy-16α-fluoroandrost-4-ene,12β,17β-dihydroxy-16α-fluoroandrost-4-ene,1α,17α-dihydroxy-16α-fluoroandrost-4-ene,1β,17α-dihydroxy-16α-fluoroandrost-4-ene,2α,17α-dihydroxy-16α-fluoroandrost-4-ene,2β,17α-dihydroxy-16α-fluoroandrost-4-ene,12α,17α-dihydroxy-16α-fluoroandrost-4-ene,12β,17α-dihydroxy-16α-fluoroandrost-4-ene,15α,17β-dihydroxy-16α-fluoroandrost-4-ene,15β,17β-dihydroxy-16α-fluoroandrost-4-ene,17β,18-dihydroxy-16α-fluoroandrost-4-ene,17β,19-dihydroxy-16α-fluoroandrost-4-ene,15α,17α-dihydroxy-16α-fluoroandrost-4-ene,15β,17α-dihydroxy-16α-fluoroandrost-4-ene,17α,18-dihydroxy-16α-fluoroandrost-4-ene,17α,19-dihydroxy-16α-fluoroandrost-4-ene, 3β,17β-dihydroxyandrost-5-ene,3β-hydroxy-7,17-dioxoandrost-5-ene, 3α-hydroxy-7,17-dioxoandrost-5-ene,3,17-dioxoandrost-5-ene, 3,17-dioxoandrost-4-ene,3,17-dioxoandrost-1,4-diene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,7β,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane,3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane,3α,16β-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3β,16α,17α-trihydroxyandrostane,3β,16β,17α-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3α,16β,17β-trihydroxyandrostane or an analog of any of the foregoingcompounds that is suitably substituted to fall within the scope of theembodiment, e.g., wherein an R¹⁰ is a hydroxyl, thiol, optionallysubstituted alkyl or a halogen such as fluorine or bromine at the 1-,2-, 4-, 6-, 7-, 9-11-, 12-, 14-, 15- or 16-position, wherein the R¹⁰ ispresent in the α-configuration or the β-configuration.

67. A method to treat, ameliorate or slow the progression of cysticfibrosis in a human comprising administering to the human an effectiveamount of a formula 1 compound of any preceeding embodiment.

68. The method of embodiment 67, wherein one or more symptoms orsyndromes are ameliorated, or wherein the progression of the disease isreduced.

69. The method of embodiment 68, wherein the one or more symptoms orsyndromes are 1, 2, 3 or more of Staphylococcus (e.g., S. aureus),Haemophilus influenzae, Pseudomonas or Burkholderia respiratory tract orlung infection or propensity to develop a detectable infection orcolonization, coughing, wheezing, cyanosis, bronchiolitis, bronchospasm,pneumothorax, hemoptysis, pancreatic exocrine insufficiency,bronchiectatic lung disease, atelectasis-consolidation, pulmonary edema,increased lung vascular hydrostatic pressure, increased lung vascularpermeability, sinusitis, respiratory insufficiency, bronchial wall orinterlobular septa thickening, reduction of forced expiratory volume in1 second, dyspnea, impaired male fertility, elevated sweat chloride,mucous plugging, tree-in-bud sign, mosaic perfusion pattern, glucoseintolerance or abnormal elevation of one or more of IL-4, IL-8, RANTES,neutrophil elastase, eosinophils, macrophages, neutrophils, eosinophilcationic protein or cysteinyl leukotrienes.

70. The method of embodiment 67, 68 or 69 wherein the method furthercomprises another suitable CF treatment, which is optionally selectedfrom oral or aerosol corticosteroid treatment, ibuprofen treatment,DNAse treatment, IL-10 treatment, diet control, vaccination againstpathogens, or chest physical therapy.

71. The method of embodiment 67, 68, 69 or 70 wherein the F1C is16α-bromoepiandrosterone, 16α-bromoepiandrosterone hemihydrate,16α-hydroxyepiandrosterone, 16β-hydroxyepiandrosterone,3α,17β-dihydroxyandrostane, 3β,17β-dihydroxyandrostane,3α,16α,17β-trihydroxyandrostane, 3α,16β,17βtrihydroxyandrostane,3β,16α,17β-trihydroxyandrostane, 3β,16β,17β-trihydroxyandrostane, or anester, carbonate or other analog of any of these compounds that canconvert to the compound by metabolism or hydrolysis.

72. A method to prevent, treat or ameliorate neutropenia in a humancomprising administering to the human an effective amount of a formula 1compound of any of embodiments 1-66, wherein the neutropenia ispostinfectious neutropenia, autoimmune neutropenia, chronic idiopathicneutropenia or a neutropenia resulting from or potentially resultingresult from a cancer chemotherapy, chemotherapy for an autoimmunedisease, an antiviral therapy, radiation exposure, tissue or solid organallograft or xenograft rejection or immune suppression therapy in tissueor solid organ transplantation or aging or immunesenescence.

73. The method of embodiment 72 wherein one R⁴ is in the β-configurationor the α-configuration and is —NH₂, a substituted amine or an amide,which is optionally selected from —NH₂, —NHCH₃, —N(CH₃)₂, —NHR^(PR),—NH—C(O)—H and —NH—C(O)-optionally substituted alkyl, e.g.,—NH—C(O)—CH₃.

74. The method of embodiment 73 wherein the other R⁴ is —H, optionallysubstituted alkyl, —CN, —SCN or —OH.

75. The method of embodiment 72 wherein the F1C is3β-hydroxy-17β-aminoandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16,16-difluoro-17β-aminoandrost-5-ene,3β,16α-dihydroxy-17β-aminoandrost-5-ene,3β,16β-dihydroxy-17β-aminoandrost-5-ene,3β-hydroxy-16,16-dimethyl-17β-aminoandrost-5-ene, an ester or carbonateof any of these compounds or an analog of any of the foregoing compoundswhere the double bond at the 5-6 position is absent and a hydrogen orother R¹⁰ moiety is present at the 5-position in the α- orβ-configuration and/or wherein the hydroxyl group (or ester or carbonateanalog) at the 3-position is present in the α-configuration.

76. A compound of formula 1 as defined in embodiment 1.

77. The compound of embodiment 76 wherein one R³ is a halogen, the otherR³ is not a halogen and one R⁴ is —NH₂, a substituted amine, an N-linkedamino acid, —N(R^(PR))₂ or an amide, where R^(PR) independently ortogether are —H or a protecting group.

78. The compound of embodiment 77 wherein one R⁴ is —NH₂.

79. The compound of embodiment 77 wherein the compound is3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene,3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3α-hydroxy-16β-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-4-ene,3β-hydroxy-16β-fluoro-17β-aminoandrost-4-ene,3α-hydroxy-16α-fluoro-17β-aminoandrost-4-ene,3α-hydroxy-16β-fluoro-17β-aminoandrost-4-ene,3β-hydroxy-16α-fluoro-17β-aminoandrostane,3β-hydroxy-16β-fluoro-17β-aminoandrostane,3α-hydroxy-16α-fluoro-17β-aminoandrostane,3α-hydroxy-16β-fluoro-17β-aminoandrostane,3β-hydroxy-16α-fluoro-17β-amino-5β-androstane,3β-hydroxy-16β-fluoro-17β-amino-5β-androstane,3α-hydroxy-16α-fluoro-17β-amino-5β-androstane,3α-hydroxy-16β-fluoro-17β-amino-5β-androstane or an analog of any ofthese compounds wherein (1) the compound is substituted with an R¹⁰moiety other than —H at the 1, 2, 4, 6, 7, 11, 12, 14 or 15 positionand/or (2) the compound is substituted at one or two of the 2, 11 or 15positions with an independently selected —O—, —S— or —NH-moiety thatreplaces the one or two —CH₂— moieties.

80. A composition comprising a compound of formula 1 as defined in anypreceding embodiment and one, two, three, four, five or more excipients.

81. A method to treat or to reduce the severity of a chronic allergy oran atopic disease, or one or more symptoms of the chronic allergy oratopic disease in a subject in need thereof, comprising administering aneffective amount of a formula 1 compound of embodiment 1, wherein

one R¹ is, or both R¹ together are, —OH, —OR^(PR), —SR^(PR),—O—Si—(R¹³)₃, —COOH, —OSO₃H, —OPO₃H, ═O, ═S, an ester, a thioester, athionoester, a phosphoester, a phosphothioester, a phosphonoester, aphosphiniester, a sulfite ester, a sulfate ester, an amide, an aminoacid, a peptide, an ether, a thioether, a carbonate or a carbamate, andthe other R¹ is independently chosen; and one R⁴ is, or both R⁴ togetherare, —OH, —OR^(PR), —SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS,—CN, —SCN, —NO₂, —NH₂, —COOH, —OSO₃H, —OPO₃H, ═O, ═S, ═N—OH,═N—O-optionally substituted alkyl, an ester, a thioester, a thionoester,a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester,a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, anether, a thioether, an acyl group, a thioacyl group, a carbonate or acarbamate, and the other R⁴ is independently chosen.

82. The method of embodiment 81 wherein the compound is16α-bromoepiandrosterone, 16α-bromoepiandrosterone hemihydrate,16α-iodoepiandrosterone, 16-oxoepiandrosterone, 16-oxoandrosterone,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,16βdihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or ananalog of any of these compounds that is (1) 2-oxa or 11-oxasubstituted, (2) substituted at the 7-position with an α-halogen,β-halogen, α-hydroxyl, β-hydroxyl or oxo moiety, (3) a D-ring homoanalog, (4) a 19-nor analog and/or (5) an analog of any of the foregoingcompounds that is substituted with an R¹⁰ substituent disclosed herein,e.g., wherein the R¹⁰ is a hydroxyl, thiol, optionally substituted alkylor a halogen such as fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-,12-, 14-, 15- or 16-positions, wherein the R¹⁰, e.g., the hydroxyl,thiol, optionally substituted alkyl or halogen is present in theα-configuration or the β-configuration.

83. The method of embodiment 81 or 82 wherein the level or activity ofIgE in the subject is at least transiently detectably reduced, e.g.,shortly after allergen exposure (such as within about 1 hour to about 1week) or at one or more later times.

84. A method to increase the efficacy of an immune response to dendriticcells in a subject, comprising (1) contacting for a sufficient time aneffective amount of a formula 1 compound of any of embodiments 1-66 andan effective amount of a non-self antigen with the subject's dendriticcells in vitro, (2) optionally expanding the dendritic cells in vitro inthe presence or absence of the formula 1 compound and/or the antigen,(3) infusing the dendritic cells into the subject, (4) optionallyadministering an effective amount of the formula 1 compound to thesubject and/or optionally administering an effective amount of thenon-self antigen to the subject.

85. The method of embodiment 84 wherein the non-self antigen comprisesan antigen derived or obtained from an infectious agent or from amalignant cell or a pre-malignant cell, wherein the malignant orpre-malignant cell is from the subject or is from another individual ofthe same species as the subject.

86. The method of embodiment 84 or 85 wherein one R¹ is, or both R¹together are, —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, —COOH, —OSO₃H,—OPO₃H, ═O, ═S, an ester, a thioester, a thionoester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, a carbonate or a carbamate, and the other R¹ is independentlychosen; and one R⁴ is, or both R⁴ together are, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, anester, a thioester, a thionoester, a phosphoester, a phosphothioester, aphosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, anamide, an amino acid, a peptide, an ether, a thioether, an acyl group, athioacyl group, a carbonate or a carbamate, and the other R⁴ isindependently chosen.

87. The method of embodiment 86 wherein the compound is3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,17β-dihydroxyandrost-1,5-diene,3β,7β,17β-trihydroxyandrost-1,5-diene,3β,17β-dihydroxy-16-haloandrost-5-ene,3β,7β,17β-trihydroxy-16-haloandrost-5-ene,16α-fluoro-17-oxoandrost-5-ene,3α-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 16α-bromoepiandrosterone,16α-bromoepiandrosterone hemihydrate, 16α-iodoepiandrosterone,16-oxoepiandrosterone, 16-oxoandrosterone,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,16β-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or ananalog of any of these compounds that is (1) 11-oxa substituted or 2-oxasubstituted if no double bond is present at the 1-2 position, (2)substituted at the 7-position with an α-halogen, β-halogen, α-hydroxyl,β-hydroxyl or oxo moiety (3), (3) a D-ring homo analog, (4) a 19-noranalog and/or (5) an analog of any of the foregoing compounds that issubstituted with an R¹⁰ substituent disclosed herein, e.g., wherein theR¹⁰ is a hydroxyl, thiol, optionally substituted alkyl or a halogen suchas fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or16-positions, wherein the R¹⁰, e.g., the hydroxyl, thiol, optionallysubstituted alkyl or halogen is present in the α-configuration or theβ-configuration.

88. A method to increase the efficacy of allergy vaccinations in asubject having an allergy, comprising (1) at an effective time before orduring vaccination of the subject with an allergen, administering to thesubject an effective amount of a formula 1 compound of embodiment 1, (2)optionally administering to the subject an effective amount of theformula 1 compound daily or intermittently for 2, 3, 4, 5, 6, 7, 14 ormore days after the vacination of step (1), (3) after passage ofsufficient time, repeating step (1) and (4) after passage of sufficienttime, optionally repeating steps (1), (3) and/or (2).

89. The method of embodiment 88 wherein the subject has a chronicallergy or atopic disease, optionally selected from allergic rhinitis,psoriasis, eczema, gastrointestinal allergies, atopic dermatitisconditions, allergic asthma, food allergies and hay fever and (1)wherein the level of IgE in the subject is at least transientlydetectably reduced during or after exposure to the allergen, or (2)wherein the total number of anti-allergic vaccinations that are neededto reduce allergy reactions or symptoms to allergen exposure is reducedor there is an increase in the quality or length of an effectiveresponse to allergen vaccination or there is an increase the proportionof subjects in which allergy vaccination is effective.

90. The method of embodiment 88 or 89 wherein one R¹ is, or both R¹together are, —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, —COOH, —OSO₃H,—OPO₃H, ═O, ═S, an ester, a thioester, a thionoester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, a carbonate or a carbamate, and the other R¹ is independentlychosen; and one R⁴ is, or both R⁴ together are, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, anester, a thioester, a thionoester, a phosphoester, a phosphothioester, aphosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, anamide, an amino acid, a peptide, an ether, a thioether, an acyl group, athioacyl group, a carbonate or a carbamate, and the other R⁴ isindependently chosen.

91. The method of embodiment 90 wherein the compound is3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,17β-dihydroxyandrost-1,5-diene,3β,7β,17β-trihydroxyandrost-1,5-diene,3β,17β-dihydroxy-16-haloandrost-5-ene,3β,7β,17β-trihydroxy-16-haloandrost-5-ene,16α-fluoro-17-oxoandrost-5-ene,3α-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 16α-bromoepiandrosterone,16α-bromoepiandrosterone hemihydrate, 16α-iodoepiandrosterone,16-oxoepiandrosterone, 16-oxoandrosterone,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,16(3-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or ananalog of any of these compounds that is (1) 11-oxa substituted or 2-oxasubstituted if no double bond is present at the 1-2 position, (2)substituted at the 7-position with an α-halogen, β-halogen, α-hydroxyl,β-hydroxyl or oxo moiety, (3) a D-ring homo analog, (4) a 19-nor analogand/or (5) an analog of any of the foregoing compounds that issubstituted with an R¹⁰ substituent disclosed herein, e.g., wherein theR¹⁰ is a hydroxyl, thiol, optionally substituted alkyl or a halogen suchas fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or16-positions, wherein the R¹⁰, e.g., the hydroxyl, thiol, optionallysubstituted alkyl or halogen is present in the α-configuration or theβ-configuration.

92. A method to prevent, treat or to reduce the severity of vascular ormicrovascular occlusions in human sickle cell or thalassemia diseases,comprising administering to the patient an effective amount of a formula1 compound of any of embodiments 1-66.

93. The method of embodiment 92 further comprising daily or intermittentadministration of the formula 1 compound.

94. The method of embodiment 92 or 93 further comprising monitoring thesubject's blood cell status to determine if further administration ofthe formula 1 compound is desirable, and, if further treatment isdesirable, administering to the patient an effective amount of theformula 1 compound.

95. The method of embodiment 92, 93 or 94 wherein the frequency ofobserved vascular occlusion events in the subject or the severity of thesubject's symptoms of vascular occlusions is at least transientlydetectably reduced.

96. The method of embodiment 92, 93, 95 or 95 wherein one R¹ is, or bothR¹ together are, —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, an ester, a thioester, a thionoester, aphosphoester, a phosphothioester, a phosphonoester, a phosphiniester, asulfite ester, a sulfate ester, an amide, an amino acid, a peptide, anether, a thioether, a carbonate or a carbamate, and the other R¹ isindependently chosen; and one R⁴ is, or both R⁴ together are, —OH,—OR^(PR), —SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN,—NO₂, —NH₂, —COOH, —OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionallysubstituted alkyl, an ester, a thioester, a thionoester, a phosphoester,a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester,a sulfate ester, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate or a carbamate,and the other R⁴ is independently chosen.

97. The method of embodiment 90 wherein the compound is3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,17β-dihydroxyandrost-1,5-diene,3β,7β,17β-trihydroxyandrost-1,5-diene,3β,17β-dihydroxy-16-haloandrost-5-ene,3β,7β,17β-trihydroxy-16-haloandrost-5-ene,16α-fluoro-17-oxoandrost-5-ene,3α-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β,17βdihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 16α-bromoepiandrosterone,16α-bromoepiandrosterone hemihydrate, 16α-iodoepiandrosterone,16-oxoepiandrosterone, 16-oxoandrosterone,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,16β-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or ananalog of any of these compounds that is (1) 11-oxa substituted or 2-oxasubstituted if no double bond is present at the 1-2 position, (2)substituted at the 7-position with an α-halogen, β-halogen, α-hydroxyl,β-hydroxyl or oxo moiety, (3) a D-ring homo analog, (4) a 19-nor analogand/or (5) an analog of any of the foregoing compounds that issubstituted with an R¹⁰ substituent disclosed herein, e.g., wherein theR¹⁰ is a hydroxyl, thiol, optionally substituted alkyl or a halogen suchas fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or16-positions, wherein the R¹⁰, e.g., the hydroxyl, thiol, optionallysubstituted alkyl or halogen is present in the α-configuration or theβ-configuration.

98. A method to identify a compound that modulates the expression in acell of the level of or an activity of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ormore genes or gene products or gene transcripts in the cell, comprisingcontacting an effective amount of the compound with the cell undersuitable conditions and for a sufficient time to detectably modulate theactivity or level of the genes, or gene products in the cell, whereinthe compound is a compound of any of embodiments 1-65.

99. The method of embodiment 98 wherein the genes or gene products areoptionally selected from the group consisting of the genes or geneproducts disclosed herein.

100. The method of embodiment 98 or 99 wherein the genes or geneproducts are selected from the group consisting of USF1, c-Fos, EGR1,Cul1, RIPK2, IκBα, IκBKb, NF-κB1 p50, FCAR, c-Fos/C/EBPβ, RANTES, ICAM1,TSG (TNFAIP6), IL-2 receptor α, GRO2, GRO3, HO1, Jun B, c-Fos/JunBcomplex, JunB/ATF3 complex, c-Jun, c-Fos/c-Jun complex, ATF-3, MMP1,TSG-6 (TNFAIP3), EGR1, TGFβ, ATF-3/c-Jun complex, c-Fos, MMP3, IL-8,STAT5A, STAT5B, CDKN1A, IFNγ receptor 2 (IFNγR2), T-bet, C reactiveprotein, immunoglobulin E, an AP-1 family protein, SOD2, GATA-3, Jak2,Tyk2, stat1, stat3, stat4, stat5, stat6, MIP-1α, MIP-2, IP-10, MCP-1,TNF-α, TNF-β, LT-β, IFN-α, IFN-β, TGF-β1, NF-κB, IL-1α, IL-1β, IL-4,IL-6, IL-10, IL-12 receptor β1, IL-12p35, IL-12p40, IL-23 and IL-23receptor.

101. The method of embodiment 98, 99 or 100 wherein the level oractivity of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, about 30, about 50, about 100, about 150, about 200, about250, about 300, about 500, about 700 or about 1000 of the genes or geneproducts is detectably modulated at least transiently.

102. The method of any of embodiments 98-101 wherein the level or anactivity of the gene product is a detectable increase in the level ofthe mRNA, the protein or one or more biological activities associatedwith the gene product.

103. The method of embodiment 102 wherein the increase is a transientincrease of about 1 hour to about 12 hours.

104. The method of embodiment 102 wherein the level or an activity ofthe gene product is a detectable decrease in the level of the mRNA, theprotein or one or more biological activities associated with the geneproduct.

105. The method of embodiment 104 wherein the increase is a transientdecrease of about 1 hour to about 12 hours.

106. The method of any of embodiments 98-101 wherein the modulation isan increase or a decrease of at least about 2-fold to about 1000-fold inthe level or an activity of the mRNA, the protein or at least onebiological activity associated with the gene product.

107. The method of any of embodiments 98-106 wherein one R¹ is, or bothR¹ together are, —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, an ester, a thioester, a thionoester, aphosphoester, a phosphothioester, a phosphonoester, a phosphiniester, asulfite ester, a sulfate ester, an amide, an amino acid, a peptide, anether, a thioether, a carbonate or a carbamate, and the other R¹ isindependently chosen; and one R⁴ is, or both R⁴ together are, —OH,—OR^(PR), —SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN,—NO₂, —NH₂, —COOH, —OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionallysubstituted alkyl, an ester, a thioester, a thionoester, a phosphoester,a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester,a sulfate ester, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate or a carbamate,and the other R⁴ is independently chosen.

108. The method of any of embodiments 98-106 wherein the formula 1compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate,16α-fluoro-3β-hydroxy-5α-androstan-17-one,16α-chloro-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-fluoro-3β-hydroxy-5α-androstan-17-one,16β-chloro-3β-hydroxy-5α-androstan-17-one,16α,3β-dihydroxy-5α-androstan-17-one,16β,3α-dihydroxy-5α-androstan-17-one,16α,3α-dihydroxy-5α-androstan-17-one,16β,3α-dihydroxy-5α-androstan-17-one,16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate,3α-hydroxy-16α-fluoroandrostane-17-one,3β-hydroxy-16α-fluoroandrostane-17-one,17α-hydroxy-16α-fluoroandrostane-3-one,17β-hydroxy-16α-fluoroandrostane-3-one,17α-hydroxy-16α-fluoroandrostane-4-one,17β-hydroxy-16α-fluoroandrostane-4-one,17α-hydroxy-16α-fluoroandrostane-6-one,17β-hydroxy-16α-fluoroandrostane-6-one,17α-hydroxy-16α-fluoroandrostane-7-one,17β-hydroxy-16α-fluoroandrostane-7-one,17α-hydroxy-16α-fluoroandrostane-11-one,17β-hydroxy-16α-fluoroandrostane-11-one, 16α-fluoroandrost-5-ene-17-one,7α-hydroxy-16α-fluoroandrost-5-ene-17-one,7β-hydroxy-16α-fluoroandrost-5-ene-17-one,4α-hydroxy-16α-fluoroandrost-5-ene-17-one,3α-hydroxy-16α-fluoroandrost-5-ene-17-one,3β-hydroxy-16α-fluoroandrost-5-ene-17-one,4β-hydroxy-16α-fluoroandrost-5-ene-17-one,6α-hydroxy-16α-fluoroandrost-5-ene-17-one,6β-hydroxy-16α-fluoroandrost-5-ene-17-one,11α-hydroxy-16α-fluoroandrost-5-ene-17-one,11β-hydroxy-16α-fluoroandrost-5-ene-17-one,4α,17β-dihydroxy-16α-fluoroandrost-5-ene,4β,17β-dihydroxy-16α-fluoroandrost-5-ene,6α,17β-dihydroxy-16α-fluoroandrost-5-ene,6β,17β-dihydroxy-16α-fluoroandrost-5-ene,11α,17β-dihydroxy-16α-fluoroandrost-5-ene,11β,17β-dihydroxy-16α-fluoroandrost-5-ene,4α,17α-dihydroxy-16α-fluoroandrost-5-ene,4β,17α-dihydroxy-16α-fluoroandrost-5-ene,6α,17α-dihydroxy-16α-fluoroandrost-5-ene,6β,17α-dihydroxy-16α-fluoroandrost-5-ene,11α,17α-dihydroxy-16α-fluoroandrost-5-ene,11β,17α-dihydroxy-16α-fluoroandrost-5-ene,7α,17β-dihydroxy-16α-fluoroandrost-5-ene,7β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17α-dihydroxy-16α-fluoroandrost-5-ene,3β,17α-dihydroxy-16α-fluoroandrost-5-ene,1α,17β-dihydroxy-16α-fluoroandrost-5-ene,1β,17β-dihydroxy-16α-fluoroandrost-5-ene,2α,17β-dihydroxy-16α-fluoroandrost-5-ene,2β,17β-dihydroxy-16α-fluoroandrost-5-ene,12α,17β-dihydroxy-16α-fluoroandrost-5-ene,12β,17β-dihydroxy-16α-fluoroandrost-5-ene,1α,17α-dihydroxy-16α-fluoroandrost-5-ene,1β,17α-dihydroxy-16α-fluoroandrost-5-ene,2α,17α-dihydroxy-16α-fluoroandrost-5-ene,2β,17α-dihydroxy-16α-fluoroandrost-5-ene,12α,17α-dihydroxy-16α-fluoroandrost-5-ene,12β,17α-dihydroxy-16α-fluoroandrost-5-ene,15α,17β-dihydroxy-16α-fluoroandrost-5-ene,15β,17β-dihydroxy-16α-fluoroandrost-5-ene,17β,18-dihydroxy-16α-fluoroandrost-5-ene,17β,19-dihydroxy-16α-fluoroandrost-5-ene,15α,17α-dihydroxy-16α-fluoroandrost-5-ene,15β,17α-dihydroxy-16α-fluoroandrost-5-ene,17α,18-dihydroxy-16α-fluoroandrost-5-ene,17α,19-dihydroxy-16α-fluoroandrost-5-ene,16α-fluoroandrost-4-ene-17-one,7α-hydroxy-16α-fluoroandrost-4-ene-17-one,7β-hydroxy-16α-fluoroandrost-4-ene-17-one,3α-hydroxy-16α-fluoroandrost-4-ene-17-one,3β-hydroxy-16α-fluoroandrost-4-ene-17-one,4α-hydroxy-16α-fluoroandrost-4-ene-17-one,4β-hydroxy-16α-fluoroandrost-4-ene-17-one,6α-hydroxy-16α-fluoroandrost-4-ene-17-one,6β-hydroxy-16α-fluoroandrost-4-ene-17-one,11α-hydroxy-16α-fluoroandrost-4-ene-17-one,11β-hydroxy-16α-fluoroandrost-4-ene-17-one,4α,17β-dihydroxy-16α-fluoroandrost-4-ene,4β,17β-dihydroxy-16α-fluoroandrost-4-ene,6α,17β-dihydroxy-16α-fluoroandrost-4-ene,6β,17β-dihydroxy-16α-fluoroandrost-4-ene,11α,17β-dihydroxy-16α-fluoroandrost-4-ene,11β,17β-dihydroxy-16α-fluoroandrost-4-ene,4α,17α-dihydroxy-16α-fluoroandrost-4-ene,4β,17α-dihydroxy-16α-fluoroandrost-4-ene,6α,17α-dihydroxy-16α-fluoroandrost-4-ene,6β,17α-dihydroxy-16α-fluoroandrost-4-ene,11α,17α-dihydroxy-16α-fluoroandrost-4-ene,11β,17α-dihydroxy-16α-fluoroandrost-4-ene,7α,17β-dihydroxy-16α-fluoroandrost-4-ene,7β,17β-dihydroxy-16α-fluoroandrost-4-ene,3α,17β-dihydroxy-16α-fluoroandrost-4-ene,3β,17β-dihydroxy-16α-fluoroandrost-4-ene,3α,17α-dihydroxy-16α-fluoroandrost-4-ene,3β,17α-dihydroxy-16α-fluoroandrost-4-ene,1α,17β-dihydroxy-16α-fluoroandrost-4-ene,1β,17β-dihydroxy-16α-fluoroandrost-4-ene,2α,17β-dihydroxy-16α-fluoroandrost-4-ene,2β,17β-dihydroxy-16α-fluoroandrost-4-ene,12α,17β-dihydroxy-16α-fluoroandrost-4-ene,12β,17β-dihydroxy-16α-fluoroandrost-4-ene,1α,17α-dihydroxy-16α-fluoroandrost-4-ene,1β,17α-dihydroxy-16α-fluoroandrost-4-ene,2α,17α-dihydroxy-16α-fluoroandrost-4-ene,2β,17α-dihydroxy-16α-fluoroandrost-4-ene,12α,17α-dihydroxy-16α-fluoroandrost-4-ene,12β,17α-dihydroxy-16α-fluoroandrost-4-ene,15α,17β-dihydroxy-16α-fluoroandrost-4-ene,15β,17β-dihydroxy-16α-fluoroandrost-4-ene,17β,18-dihydroxy-16α-fluoroandrost-4-ene,17β,19-dihydroxy-16α-fluoroandrost-4-ene,15α,17α-dihydroxy-16α-fluoroandrost-4-ene,15β,17α-dihydroxy-16α-fluoroandrost-4-ene,17α,18-dihydroxy-16α-fluoroandrost-4-ene,17α,19-dihydroxy-16α-fluoroandrost-4-ene, 3β,17β-dihydroxyandrost-5-ene,3β-hydroxy-7,17-dioxoandrost-5-ene, 3α-hydroxy-7,17-dioxoandrost-5-ene,3,17-dioxoandrost-5-ene, 3,17-dioxoandrost-4-ene,3,17-dioxoandrost-1,4-diene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,7β,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane,3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane,3α,16β-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3β,16α,17α-trihydroxyandrostane,3β,16β,17α-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3α,16β,17β-trihydroxyandrostane or an analog of any of these compoundsthat is (1) 11-oxa substituted or 2-oxa substituted if no double bond ispresent at the 1-2 position, (2) substituted at the 7-position with anα-halogen, β-halogen, α-hydroxyl, β-hydroxyl or oxo moiety, (3) a D-ringhomo analog, (4) a 19-nor analog and/or (5) an analog of any of theforegoing compounds that is substituted with an R¹⁰ substituentdisclosed herein, e.g., wherein the R¹⁰ is a hydroxyl, thiol, optionallysubstituted alkyl or a halogen such as fluorine or bromine at the 1-,2-, 4-, 6-, 9-11-, 12-, 14-, 15- or 16-positions, wherein the R¹⁰, e.g.,the hydroxyl, thiol, optionally substituted alkyl or halogen is presentin the α-configuration or the β-configuration.

109. A method to enhance the healing of a trauma or an acute injury in asubject who has experienced or who is expected to experience a trauma oran acute injury comprising administering an effective amount of acompound to the subject, wherein the compound is (1)3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene, a16-halo analog of either compound, a 16-hydroxy analog of eithercompound, an 11-oxa analog of either compound, a 2-oxa analog of eithercompound, an ester or a carbonate of either compound, a derivative ofeither compound that can convert to either compound by hydrolysis or bymetabolism or (2) a formula 1 compound of any of embodiments 1-66.

110. The method of embodiment 109 wherein the subject will experience orhas experienced an immune suppressive event within about 2-3 weeks orabout 3-4 weeks of the occurrence of the trauma or acute injury, whereinthe immune suppressive event is exposure of the subject to an immunesuppressive amount of ionizing radiation.

111. The method of embodiment 110 wherein the ionizing radiationexposure is about 0.3 Gy to about 30 Gy of the ionizing radiation.

112. The method of embodiment 110 wherein the radiation exposure isabout 0.5 Gy to about 8 Gy of the ionizing radiation.

113. The method of embodiment 109 wherein the subject has experienced animmune suppressive event within 3 weeks of the occurrence of the traumaor acute injury, wherein the immune suppressive event is selected froman immune suppressive amount of an immunosuppressive chemotherapy.

114. The method of embodiment 113 wherein the immunosuppressivechemotherapy is an immunosuppressive cancer chemotherapy, animmunosuppressive amtimicrobial therapy or an immunosuppressiveglucocorticoid therapy.

115. The method of embodiment 113 wherein the immunosuppressive cancerchemotherapy is treatment of the subject with an immunosuppressiveamount of cyclophosphamide, 5-fluorouracil or a platinum compoundoptionally selected from cisplatin and carboplatin.

116. The method of embodiment 113 wherein the immunosuppressiveglucocorticoid chemotherapy is treatment of the subject with animmunosuppressive amount of dexamethasone, prednisone, hydrocortisone orcortisol.

117. The method of any of embodiments 109-116 wherein the subject is ahuman or a primate.

118. The method of any of embodiments 109-117 wherein the formula 1compound has the structure

119. The method of embodiment 118 wherein the compound is3β-hydroxy-17β-aminoandrost-5-ene.

120. The method of embodiment 118 wherein the compound is3β-hydroxy-17β-amino-17α-optionally substituted alkyl-androst-5-ene,3β-hydroxy-9α-fluoro-17β-aminoandrost-5-ene or3β-hydroxy-17β-amino-19-norandrost-5-ene.

121. The method of any of embodiments 109-117 wherein the compound is3β,17β-dihydroxyandrost-5-ene.

122. A method to modulate the expression of one or more transcriptionfactors or enzymes in a subject who has a dysregulated oxidative stresscondition comprising administering an effective amount of a compound tothe subject, wherein the compound is (1)3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,17β-dihydroxy-16α-haloandrostane,3α,17β-dihydroxy-16α-haloandrostane,3β,17β-dihydroxy-16α-bromoandrostane,3α,17β-dihydroxy-16α-bromoandrostane,3β-hydroxy-16α-bromoandrostane-17-one,3β-hydroxy-16α-bromoandrostane-17-one hemihydrate,3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,17β-dihydroxy-16α-haloandrost-5-ene,3α,17β-dihydroxy-16α-haloandrost-5-ene,3β,16α,17β-trihydroxyandrost-5-ene, 3α,16α,17β-trihydroxyandrost-5-ene,an 11-oxa analog of any of these compounds, a 2-oxa analog of any ofthese compounds, a 19-nor analog of any of these compounds, a 9α-fluoroanalog of any of these compounds, or an ester or a carbonate of any ofthese compounds or analogs, or (2) a derivative of any of thesecompounds or analogs that can convert to these compounds or analogs byhydrolysis or by metabolism, or (3) a formula 1 compound of any ofembodiments 1-66.

123. The method of embodiment 122 wherein the compound modulates thelevel or activity of a transcription factor or enzyme selected from oneor more of Nrf2, a Maf protein, a thioredoxin, NQO1, GST, HO1, SOD2, thecatalytic subunit of γGCS, the regulatory subunit of γGCS and xCT.

124. The method of embodiment 122 or 123 wherein the dysregulatedoxidative stress condition is associated with exposure of the subject toa toxin that can cause cell or tissue damage or wherein elevatedoxidative stress is present in one or more of the subject's cell typesor tissues.

125. The method of embodiment 122, 123 or 124 wherein the subject has anacute or chronic inflammation condition, an acute or chronic infectionor a trauma.

126. The method of embodiment 122, 123, 124 or 125 wherein the levels oractivity of one, two or more of Nrf2, a Maf protein, a thioredoxin,NQO1, GST, HO1, the catalytic subunit of γGCS, the regulatory subunit ofγGCS and xCT is increased.

127. The method of embodiment 122, 123, 124, 125 or 126 wherein thecompound is 3β,16α,17β-trihydroxyandrostane,3α,16α,17β-trihydroxyandrostane, 3β,16α-dihydroxyandrostane-17-one or3α,16α-dihydroxyandrostane-17-one.

128. A product produced by the process of (1) contacting a F1C(s) and anexcipient or (2) contacting a composition comprising a F1C(s) and one ormore excipients with one or more additional excipients.

129. Use of a compound, composition, formulation or product of any ofembodiments 1-129 or of any species or group of F1Cs disclosed hereinfor the preparation of a medicament. The medicament can be for theprophylaxis or treatment of a disease or condition disclosed herein in asubject having or susceptible to developing the disease or condition.

130. The use of a compound, composition, formulation or product of anyof embodiments 1-129 or of any species or group of F1Cs disclosed hereinto prepare a medicament for use to prevent or to treat, or to ameliorateone or more symptoms associated, with one, two or more acute or chronicdiseases or conditions disclosed herein, e.g., an infection, animmunesuppression condition, an allergy, a cardiovascular condition, ametabolic disorder, a pulmonary condition, a skin condition, aging, atrauma such as a burn or a bone fracture, immune suppression, aneurological or centeral or peripheral nervous system condition ordisorder, an unwanted or pathological inflammatory condition, toxicityor unwanted side-effects of a chemotherapy or of radiation exposure suchas a glucocorticoid treatment or a cancer chemotherapy, an autoimmunedisease or condition, a malignancy or cancer, a pre-malignant conditionor to modulate a mammal's immune response, such as enhancing a Th1response or decreasing a Th2 response, in a subject, e.g., a human or amammal, having the acute or chronic disease or condition or subject todeveloping the acute or chronic disease or condition.

131. The use of embodiment 130, wherein the infection is a viral,bacterial, fungal, yeast or parasite infection, e.g., as describedherein.

132. Use according to embodiment 130 or 131 wherein the medicament isfor intermittently administering the F1C(s) to a subject or deliveringto the subject's tissues the F1C(s), e.g., using an intermittent dosingprotocol disclosed herein.

133. Use of a compound, composition, formulation or product of any ofembodiments 1-129 or of any species or group of F1Cs disclosed herein toprepare a medicament for use to enhacnce a specific or an innate humoralor cellular response to vaccination or to the presence of 1, 2, 3, 4, 5,6 or more endogenous antigens or epitopes associated with establishingor maintaining a disease or pathogenic agent such as a tumor antigen oran antigen associated with a pathogen.

134. Use according to embodiment 133 wherein the subject's innateimmunity is enhanced.

135. Use according to embodiment 13 or 134 wherein the subject's innateor adaptive immunity is enhanced or wherein an unwanted immune responseis decreased, or wherein number or activity of one, two or more of thesubject's Th1 cells, tumor-infiltrating lymphocytes (TIL cells), NKcells, peripheral blood lymphocytes, phagocytes, monocytes, macrophage,neutrophils, eosinophils, dendritic cells, fibrocytes, astrocytes, gilalcells or stromal cells, e.g., bone marrow, lymph node or spleen stroma,are increased or activated at least transiently (e.g., for at least 10minutes to 10 days or more), which is optionally as measured by, e.g.,enhanced ³H-thymidine uptake compared to untreated controls or by anincrease in the number of the cell type in circulation or demonstrablemovement of the cell type from one tissue or compartment (e.g., skin orblood) to another tissue or compartment (e.g., blood, lymph node,spleen, Peyer's patches, GALT or thymus), or wherein the transcriptionrate, protein level or biological activity of one or more genes in thesubject's NK cells, TIL cells, phagocytes, monocytes, macrophages,neutrophils, eosinophils, dendritic cells, fibrocytes, astrocytes, gilalcells or stromal cells are detectably modulated, e.g., increased (e.g.,as measured by increased enzyme or biological activity of a biomoleculesuch as a nuclear hormone receptor such as an orphan nuclear hormonereceptor, a transcription factor, a chemokine or a cytokine, which isoptionally compared to suitable control cells or tissues).

136. A method to (a) modulate (detectably increase or decrease) theexpression of at least one immune cell antigen by an immune cell in asubject, wherein the immune cell antigen is selected from CD3, CD11c,CD14, CD16, CD19, CD25, CD38, CD56, CD62L, CD69, CD45RA, CD45RO, CD123,HLA-DR, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNFα, IGF₁ and γIFN,or (b) activate CD8⁺ T cells or CD8⁻ T cells in a subject, wherein theactivation comprises at least transiently enhanced expression of CD25 orCD69 by the T cells, or (c) increase the proportion of CD8⁺ or CD8⁻lymphokine activated killer cells in a subject's CD16⁺ cells (e.g.,CD8⁺, CD16⁺, CD38⁺ or cells CD8⁻, CD16⁺, CD38⁺), or (d) increase theproportion of (i) CD8⁻, CD16⁺ natural killer cells, (ii) CD8⁺, CD16⁺natural killer cells or (iii) CD8⁻, CD16⁺ cells that mediateantibody-dependent cell-mediated cytotoxicity, or (iv) CD8⁺, CD16⁺ cellsthat mediate antibody-dependent cell-mediated cytotoxicity, or (e)increase the proportion of dendritic cell precursors in a subject'scirculating white blood cells (e.g., Lin⁻, HLA-DR⁺, CD123⁺ or Lin⁻HLA-DR⁺, CD11c⁺ cells) or (f) increase the proportion of CD45R⁺ T cellsor CD45⁺, R0⁺ T cells in a subject's circulating white blood cells, or(g) change (increase or decrease) the proportion or relative numbers ofCD62L⁺ T cells in a subject's circulating white blood cells, or (h)increase the proportion of CD8⁺ or CD4⁺ T cells that express CD62L in asubject's circulating CD8⁺ or CD4⁺ T cells, or (i) decrease theproportion of CD8⁺ or CD4⁺ T cells that express CD62L in a subject'scirculating CD8⁺ or CD4⁺ T cells, or (j) increase the proportion ofHLA-DR⁺, CD8⁺, CD38⁺ cells in a subject's circulating white blood cells,or (k) decrease the level of IL-4 or IL-10 that is expressed by orpresent in a subject's white blood cells or in a subject's plasma (orthat is expressed after the subject's white cells are stimulated invitro), (l) at least transiently increase the number of dendritic cellprecursors or dendritic cells that are present in a subject's whiteblood cells or in a subject's plasma, or (m) enhance the capacity of animmune cell, e.g., macrophages, CD4⁺ T cells, CD8⁺ T cells to expressIL-2, IL-12 or γIFN or to activate such cells, the method comprisingadministering to the subject an effective amount of a F1C, which isoptionally present in a composition or a formulation comprising 1, 2, 3,4, 5, 6 or more pharmaceutically acceptable excipients. The F1c is anycompound as described herein, e.g., a compound of embodiments 1-66 or inany chemical structure or any compound group.

137. A method to detect or to characterize a biological response (e.g.,increased or decreased cytokine or cell surface antigen expression oractivity, increased numbers of circulating neutrophils, increasedphagocytic activity by phagocytic cells or modulation of a disease orsymptom described herein) associated with the administration of a F1C toa subject comprising (1) obtaining a first biological sample from thesubject and analyzing the sample to obtain a baseline value for theresponse, (2) administering the F1C to the subject to obtain a treatedsubject (3) within about 15 minutes to about 28 days after administeringthe F1C, obtaining a second biological sample from the treated subjectand analyzing the sample to obtain a treated value for the response, and(4) optionally comparing the control information with the experimentalinformation to detect the presence, absence, relative magnitude orabsolute magnitude of the biological response.

138. The method of embodiment 137 wherein the biological response ismodulation of CD8⁺ T cells, CD4⁺ T cells, CD8⁺ lymphokine activatedkiller cells, CD8⁻, CD16⁺ natural killer cells, circulating dendriticcell precursors, circulating dendritic cells, tissue dendritic cellprecursors, tissue dendritic cells, CD8⁺ lymphokine activated killercells, CD8⁻ lymphokine activated killer cells, CD8⁻, CD16⁺ naturalkiller cells, CD8⁺, CD16⁺ natural killer cells, CD8⁻, CD16⁺ cells thatmediate antibody-dependent cell-mediated cytotoxicity, CD8⁺, CD16⁺ cellsthat mediate antibody-dependent cell-mediated cytotoxicity, CD45RA⁺ Tcells, CD45RA⁺, CD45RO⁺ T cells, CD45RO⁺ T cells, CD8⁺, CD62L T cells,CD4⁺, CD62L⁺ T cells or HLA-DR⁺, CD8⁺, CD38⁺ T cells, monocytes,macrophages, glial cells or astrocytes, or wherein the biologicalresponse is at least transient modulation of an immune cell antigen oran immune accessory cell antigen (e.g., an adhesion molecule at thesurface of endothelial cells or a cytokine receptor at the surface of Tcells or B cells or a CD molecule, an interleukin or a cytokine,optionally selected from CD16, CD25, CD38, CD62L, CD69, CD45RA, CD45RO,IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, IGF₁ and γIFN).

139. A kit comprising a formulation that comprises a unit dosage or amultiple dosage comprising a F1C, e.g., any compound described or withinany structure disclosed herein, and one or more excipients wherein theformulation is dispensed in a suitable closed container, wherein the kitoptionally further comprises a label that provides information about oneor more of (1) the F1C's chemical structure, (2) any recommended dosingregimen, (3) any adverse effects of administering the F1C to a subjectthat are required to be disclosed and (4) the amount of the F1C that ispresent in each unit dose or in the entire container.

140. A method to treat a symptom or condition associated with one ormore delayed adverse or unwanted effects of radiation exposure ortherapy in a subject in need thereof comprising administering to thesubject, or delivering to the subject's tissues, an effective amount ofa compound of formula 1, wherein the F1C is administered or delivered tothe subject's tissues beginning at least 2 weeks after the subject hasbeen exposed to a dose of radiation that will cause or could potentiallycause the one or more delayed adverse or unwanted effects of theradiation exposure, or wherein the F1C is administered or delivered tothe subject's tissues beginning at least 2 weeks after the subject hasbeen exposed to at least one subdose of a planned course of radiationexposures that will cause or could potentially cause the one or moredelayed adverse effects or unwanted effects of the radiation exposure.

141. The method of embodiment 140 wherein the subject has received, oris anticipated to receive, a total radiation dose of at least about 0.5Gy to about 300 Gy, wherein the subject received the radiation dose in asingle dose or in two or more divided doses, e.g., a total radiationdose of at least about Gy 1 to about 12 Gy, or at least about Gy 1 toabout 8 Gy.

142. The method of embodiment 140 or 141 wherein the symptom orcondition associated with one or more delayed adverse effect ofradiation is one or more of encephalopathy, myelopathy, nausea,vomiting, diarrhea, acute inflammation, e.g., of the lung, chronicinflammation, e.g., of the lung, edema, pain, headache, depression,fever, malaise, weakness, hair loss, skin atrophy, skin ulceration, skinlesion, keratosis, telangiectasia, infection, hypoplasia, atrophy,fibrosis, pneumonitis, bone marrow hypoplasia, hemorrhage, leukopenia orthrombocytopenia.

143. The method of embodiment 140, 141 or 142 wherein the symptom orcondition associated with one or more delayed adverse or unwanted effectof the radiation exposure or therapy is caused by or associated withradiation damage to one or more of bone marrow cells, bowel epithelium,bone marrow, testicles, ovaries, brain nerves or tissue, peripheralnerves, spinal cord nerves or tissue or skin epithelium.

Variations and modifications of these embodiments, the claims and theremaining portions of this disclosure will be apparent to the skilledartisan after a reading thereof. Such variations and modifications arewithin the scope and spirit of this invention. All citations herein areincorporated herein by reference in their entirety. All citations hereinare incorporated herein by reference with specificity.

EXAMPLES

The following examples further illustrate the invention and they are notintended to limit it in any way. Variations of these examples that areincluded in the invention may include, e.g., any of the F1Cs describedherein or parts or all of any of the methods, formulations, treatmentprotocols and/or assays described herein.

Example 1

Cystic fibrosis treatment. Treatment with a F1C is conducted on humancystic fibrosis (“CF”) patients, e.g., 18 years of age or older, who mayhave two or more of the following characteristics: (1) sweat chloride≧60 mEq/L, e.g., by quantitative pilocarpine iontophoresis test, (2)homozygosity for the F508 genetic mutation, or heterozygosity for 2well-characterized mutations, e.g., as described herein, associated withCF, (3) FEV₁≧40% predicted at screening, (4) SaO₂≧90% at screening, (5)ability to perform pulmonary function tests and (6) clinical stability,with no evidence of acute upper or lower respiratory tract infection orcurrent pulmonary exacerbation. The treatment regimen consists of 1, 2,3, 4 or 5 consecutive days of once daily dosing of a F1C or placeboequivalent followed by a 40-day observation period. Daily dosages areabout 10-150 mg/day, e.g., about 25 mg/day, 50 mg/day, 75 mg/day or 100mg/day. The F1C is administered as described herein such as by aparenteral route, e.g., intramuscular or subcutaneous delivery, or bytransmucosal delivery, e.g., buccal or sublingual. A follow-up visitwill occur 6 weeks after the last treatment course to collect finalsamples for safety and activity. Patients receive, e.g., 3 treatmentcourses over a 14-week period, 6 treatment courses over a 28-week periodor more courses of treatment over a longer period. F1Cs that are usedinclude 3β-hydroxy-16α-bromo-17-oxoandrostane,3β-hydroxy-16α-bromo-17-oxoandrostane hemihydrate,3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane,3β,16α,17β-trihydroxyandrostane or 3α,16α,17β-trihydroxyandrostane oranother F1C disclosed herein. The patients are optionally monitored forthe status of their condition or in improvement of one or more CFsymptoms after dosing, e.g., reduction in the numbers of neutrophils inbronchiolar or alveolar lavage samples, e.g., about a 30%, 40%, 50% orgreater reduction, or levels of one or more CF-related inflammationmarkers, e.g., reduced levels or activity of IL-6, IL-8, IKK-β kinase orneutrophil elastase, or in the reduced occurrence, severity orprogression of infections such as a Burkholderia (Pseudomonas) cepaciainfection.

Example 2

Cyclodextrin formulation. A cyclodextrin formulation containing a F1C isprepared by mixing a sulfobutyl β-cyclodextrin and the F1C in one ormore liquids such as ethanol, DMSO, N-methylpyrrolidine, pyridine orwater. The sulfobutyl β-cyclodextrin contains one or more butylsulfonate or —O—(CH₂)₄—SO₃ ⁻Na⁺ moieties, typically about 5, 6 or 7 percyclodextrin molecule. F1Cs that contain a positive charge areespecially helpful in forming complexes with the multiple negativecharges of sulfobutyl cyclodextrin. For parenteral formulations, themaximum concentrations could be achieved at about the maximumcyclodextrin concentration that is still syringable, about 50% w:v. TheF1C can be added to a solution of sulfobutyl β-cyclodextrin at a molarratio of about 1:1, e.g., 0.5:1 to about 2:1, and stirred with orwithout heat for up to about 1 week to form the complex. The solution isoptionally filtered or sterilized before filling in vials or injectiondelivery by any route. The vials can be sterilized by radiation or bysterilie filtration. An exemplary preparation is made using 500 grams ofsulfobutyl β-cyclodextrin (about 230 mmoles) combined with about 230mmoles of the F1C. Solutions containing about 20-80 mg/mL of the F1C aretypically obtained. For pharmaceutical formulations, the complex isprepared under GMP compliance conditions. The dried complex is preparedby lyophilization and can be reconstituted, e.g., using sterile 0.9%NaCl. The cyclodextrin complex can also be dried for preparation offormulations for oral or transmucosal administration or reconstitutedwith water for parenteral delivery, e.g., by subcutaneous orintramuscular injection. F1Cs that are used include3β,17β-dihydroxyandrost-5-ene, 3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,7β,17β-trihydroxyandrost-5-ene,3β-hydroxy-3α-methyl-17β-aminoandrost-4-ene,3α-hydroxy-3β-methyl-17β-aminoandrost-4-ene and3β-hydroxy-17β-aminoandrost-5-ene.

Example 3

Inhibition of inflammation. The capacity of formula 1 compounds to limitor inhibit inflammation or symptoms of inflammation is shown usinganimal models for inflammatory bowel disease. In an exemplary protocol,groups of 3 male Wistar rats (180±20 grams) fasted for 24 hours before2,4-dinitrobenzene sulfonic acid (DNBS) or saline challenge are used.Distal colitis is induced by intra-colonic instillation of 0.5 mL of anethanolic solution of DNBS (30 mg in 0.5 mL of a 30% ethanol in salinesolution) after which 2 mL of air is injected through the cannula toensure that the solution remained in the colon. The volume used is 0.1mL per injection of 2 and 20 mg/mL of a F1C in a liquid formulation,which is administered by subcutaneous injection once a day for 6 days.The formulation contained 100 mg/mL of the F1C in a non-aqueoussuspension, e.g., 2% benzyl alcohol w/v, 0.1% Brij 96 w/v and equalvolumes of PEG 300 and propylene glycol. Concentrations of 2 mg/mL and20 mg/mL are obtained by diluting the 20 mg/mL formulation with vehiclethat lacked the F1C.

The first F1C dose is given 30 minutes after DNBS challenge.Sulfasalazine (30 mg/mL in 2% Tween 80 in distilled water) isadministered orally (PO) once a day (10 mL/kg/day) for 7 days, the firsttwo doses beginning 24 hours and 2 hours before DNBS challenge. Thepresence of diarrhea is recorded daily by examining the anal area.Animals are fasted for 24 hours prior to being sacrificed. Animals aresacrificed on day 7 or day 8 and their colons are removed and weighed.Before removal of the colon, signs of adhesion between the colon andother organs are recorded. Also, the presence of ulcerations is notedafter weighing of each colon. The “net” change of colon-to-body weight(BW) ratio is normalized relative to saline-challenged baseline group. A30% decrease in “net” colon-to-body weight ratio is consideredsignificant.

Example 4

Modulation of delayed type hypersensitivity. The capacity of F1Cs tomodulate delayed type hypersensitivity (DTH) is determined in mice.Groups of five female BALB/cByJ mice (20-25 grams) are anesthetized and1004 of a 3% solution of oxazolone is applied on day 0 to the shavedabdomen and dried. Seven days later, on day 7, the mice are challengedby applying 5 μL of oxazolone topically to each side of the right ear.The F1C (at about 20-100 mg/mL) in vehicle is administered bysubcutaneous injection (2 mg/day) one time on day 6, 24 hours before theoxazolone challenge. The vehicle as a non-aqueous suspension of the F1Cin, e.g., 2% benzyl alcohol w/v, 0.1% Brij 96 w/v and equal volumes ofPEG 300 and propylene glycol.

Dexamethasone in saline (0.2 mg/mL) is administered daily for 9 days(day −1 to 7), first dose 24 hours before sensitization, last dose atchallenge by subcutaneous injection (0.01 mg/dose, 50 μL/injection). OnDay 8, 24 hours following the oxazolone challenge, both the right andleft ear thicknesses are measured using a micrometer caliper and thedifferences are determined. The differential ear thickness is measuredas an indicator of the DTH response to topical oxazolone challenge. TheDTH response is expressed as the difference in the thickness (mm)between the right and the left ears for each animal.

The differential ear thickness in animals receiving vehicle alone is0.225 mm and treatment with dexamethasone (high dose) orcyclophosphamide reduced the DTH response (0.144 mm and 0.092 mm,respectively).

Example 5

Supression of TNF-α induced adhesion molecule expression. Therecruitment of lymphocytes to areas of inflammation and angiogenesisinvolves specific receptor-ligand interactions between cell surfaceadhesion molecules (CAMs) on lymphocytes and the vascular endothelium.The adhesion process, in both normal and pathological settings, followsa multi-step cascade that involves intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelialleukocyte adhesion molecule-1 (E-selectin) expression on endothelialcells (EC). The expression of these molecules and others on the vascularendothelium determines the efficiency with which leukocytes may adhereto the local vasculature and extravasate into the local tissue duringthe development of an inflammatory response. The local concentration ofcytokines and growth factor participate in the modulation of theexpression of these CAMs.

Tumor necrosis factor alpha (TNF-α), is a proinflammatory cytokine andstimulates all three CAMs on endothelial cells. It may be involved in awide variety of inflammatory responses, often resulting in apathological outcome. The capacity of a formula 1 compound to mediate asuppression of TNF-α induced CAM expression can be examined. A modifiedELISA assay which uses Ecs as a solid phase absorbent is employed tomeasure the amount of CAM expression on TNF-α treated Ecs whenco-stimulated with a member of the FGF family of proteins. To performthe experiment, human umbilical vein endothelial cell (HUVEC) culturesare obtained from pooled cord harvests and maintained in growth medium(EGM-2, Clonetics, San Diego, Calif.) supplemented with 10% FCS and 1%penicillin/streptomycin in a 37° C. humidified incubator containing 5%CO₂. HUVECs are seeded in 96-well plates at concentrations of about1×10⁴ cells/well in EGM medium at 37° C. for 18-24 hrs or untilconfluent. The monolayers are subsequently washed 3 times with aserum-free solution of RPMI-1640 optionally supplemented with 100 U/mLpenicillin and 100 mg/mL streptomycin, and treated with a given cytokineand/or growth 5 factor(s) for 24 h at 37° C. Following incubation, thecells are then evaluated for CAM expression.

HUVECs are grown in a standard 96 well plate to confluence. Growthmedium is removed from the cells and replaced with 90 μL of 199 Medium(10% FBS). Samples for testing and positive or negative controls areadded to the plate in triplicate (in 10 μL volumes). Plates areincubated at 37° C. for either 5 h (selectin and integrin expression) or24 h (integrin expression). Plates are aspirated to remove medium and100 pL of 0.1% paraformaldehyde-PBS (with Ca⁺ and Mg⁺⁺) is added to eachwell. Plates are held at 4° C. for 30 min. Fixative is then removed fromthe wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA and drained.Do not allow the wells to dry. 10 pL of diluted primary antibody isadded to the test and control wells. Anti-ICAM-1-Biotin,Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at aconcentration of 10 pg/ml (1:10 dilution of 0.1 mg/ml stock antibody).Cells are incubated at 37° C. for 30 min. in a humidified environment.Wells are washed ×3 with PBS (with Ca, Mg) and 0.5% BSA. Then add 20 pLof diluted ExtrAvidin-Alkaline Phosphotase (1:5,000 dilution) to eachwell and incubate at 37° C. for 30 min. Wells are washed ×3 with PBS(with Ca, Mg) and 0.5% BSA. 1 tablet of p-Nitrophenol Phosphate pNPP isdissolved in 5 mL of glycine buffer (pH 10.4). 100 pl of pNPP substratein glycine buffer is added to each test well. Standard wells intriplicate are prepared from the working dilution of theExtrAvidin-Alkaline Phosphotase in glycine buffer: 5 pL of each dilutionis added to triplicate wells and the resulting AP content in each wellis 5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 pl of pNNP reagent is then beadded to each of the standard wells. The plate is incubated at 37° C.for 4 h. A volume of 50 pL of 3M NaOH is added to all wells. The resultsare quantified on a plate reader at 405 nm. The background subtractionoption is used on blank wells filled with glycine buffer only. Thetemplate is set up to indicate the concentration of AP-conjugate in eachstandard well. Results are indicated as amount of bound APconjugate ineach sample.

Example 6

Effects on the CNS. The effects of the formula 1 compounds on memory,learning, motor function or the status of a neurological condition orneurodegeneration condition are assayed using standard methods. Forexample, aged, two year old mice are tested in the Morris water mazeprocedure by training the mice to locate a pedestal in less than 15seconds in three consecutive trials. Immediately upon completion oftraining one group of mice is treated with a formula 1 compound (5-30mg/kg) and a second group is treated with a placebo. The treatmentcomprises one, two or three intraperitoneal, subcutaneous, intramuscularor intravenous injections of the formula 1 compound and the vehicleplacebo. The injections are given once per day. Two weeks aftertreatment, the time to rescue is timed in the Morris water mazeprocedure and the control result is compared to the placebo control. Theuse of Morris water maze and other procedures to measure the effect ofvarious conditions or compounds on learning, memory or neurologicalconditions have been described, see e.g., R. Gerlai Trends Neurosci.1996, 19:177-181, J. L. W. Lau et al., Proc. Nat'l. Acad. Sci. 2001,98:4716-4721, U.S. Pat. Nos. 6,348,489, 6,251,942 and 6,277,886.

Scopolamine induced amnesia is examined essentially as follows. Groupsof 13 to 16 C57BL76 mice (about 35 gm) are trained in the Morris watermaze procedure to locate a pedestal in less than 15 seconds in threeconsecutive trials. Immediately upon completion of training the mice ineach of three groups are treated with scopolamine (1 mg/kg), scopolamineplus a formula 1 compound at one or more dosages (e.g., about 5-50mg/kg), and scopolamine plus a placebo. The treatment comprises one, twoor three intraperitoneal, subcutaneous, intramuscular or intravenousinjections of the formula 1 compound and the vehicle placebo. Theinjections are given once per day. Six days after treatment the averagetime (sec) to rescue is timed using the Morris water maze procedure andthe results from each group are compared. Results for a F1C such as3α,17β-dihydroxy-16α-fluoroandrost-5-ene or3β-hydroxy-17β-aminoandrost-5-ene are optionally compared to the resultsthat are obtained in these protocols using another control compound,e.g., (S)-(−)-N-propargyl-1-aminoindan or nefiracetam, or another F1C.

Example 7

Ischemia treatment. The capacity of F1Cs to limit injury associated withischemia and reperfusion is determined in an animal model essentially asfollows. Male Sprague-Dawley rats weighing 130-170 g are randomlyassigned to no pre-treatment, vehicle pre-treatment or formula 1compound pre-treatment using one or more dosages, e.g., about 1-10mg/kg. Animals are treated with vehicle or F1C the day before and theday of surgery. Anesthesia is induced with intraperitoneal pentobarbital(60-70 mg/kg). The rats are placed on a heating pad, and bodytemperature is maintained at about 36° C. Detection of the cremastermuscle on its neurovascular pedicle is performed essentially accordingto conventional techniques, e.g., Anderson, G. L. et al., MicrovascularRes. 1988 36:56-63, Siemionow, M. et al., Microcirc. Endoth. Lymphatics1991 7:183-197, Siemionow, M. et al., J. Hand Surgery 1993 18A:963-971.

Briefly, a skin incision is made from the anterior iliac spine to thetip of the scrotum. The testis with cremaster muscle intact is thendissected away from the scrotum. An opening of 1 cm is made on theventral surface of the cremaster, and the testis and spermatic cord areremoved. Under a microscope, the neurovascular pedicle, consisting ofthe pubic-epigastric arteries, vein, and genitofemoral nerve, is thencompletely isolated by dissecting to the origin of the vessels from theexternal iliac artery and vein. The front wall of the cremaster musclesac is opened and the island cremaster muscle flap is prepared forintravital videomicroscopy. The rat is secured on a tissue bath, and thecremaster muscle flap is spread over the coverglass in the opening atthe bottom of the bath and fixed with 5-0 silk sutures. It is thentransilluminated from below, using a fiber optic tungsten lamp. Themuscle is kept moist and covered with impermeable plastic film. Thetissue bath, designed specifically for temperature control, is filledwith 0.9% saline and the temperature maintained at between 35-36° C. Themicroscope is equipped with a color video camera. The video image of themicrocirculation is displayed on a 19″ monitor, where the finalmagnification is 1800×. Measurement of microvascular activity isrecorded after isolation of the muscle to establish the pre-ischemiabaseline. After proper positioning of clamps to completely shut downblood flow to the muscle flap, the duration of the ischemic period issix hours. Following removal of clamps to induce reperfusion injury,activity in the microvasculature is measured at e.g., 30, 60 and 90minutes post-reperfusion. In all experimental subjects, ischemia isfollowed by reflow and then by an initial period of flow of bloodthrough the microcirculation. This burst of circulatory activity isfollowed by marked reperfusion injury that induces loss of flow.

One or more of the following parameters are used to evaluate the stateof the cremaster muscle microvasculatory system prior to ischemia andafter reperfusion. The density of perfused capillaries in each of threeflap regions is measured by counting the number of flowing capillariesin proximity to the preselected post-capillary venule. Nine visualfields of capillaries are counted at each postcapillary venule site, fora total of 27 fields per cremaster muscle flap.

A leukocyte count in postcapillary venules is taken using video scans ofthree pre-selected post-capillary venules in proximal, middle and distalflap regions. For each venule, the number of leukocytes rolling throughthe lumen, the number adhering to the endothelium and the numbermigrating across the endothelium over a two-minute period are recorded.Results are optionally obtained for rollers, strikers and diapedesis.

Red blood cell velocities in first order and second order arterioles aremeasured. Red blood cell velocities are recorded in the main arteriolesof the cremaster flap using an optical Doppler velocimeter. Results areobtained for velocity of venous and arterial blood.

In an exemplary protocol, six rats are untreated and six rats arepre-treated with vehicle. Under conditions of six hours of ischemia and90 minutes of reperfusion, the absolute number of rolling, sticking andtransmigrated leukocytes is determined within 60 minutes of reperfusionand at 90 minutes. Rats are pre-treated with a formula 1 compound bysubcutaneous injection the day before and the day of surgery to measureany protective effect of the therapy. One or more of the threeparameters are determined and are compared to normal values. Theendothelial-adherent properties compared to baseline values areoptionally determined, using numbers of rolling, sticking andtransmigrating leukocytes. Red cell velocities in second orderarterioles are compared to normal rates of flow at, e.g., 90 minutespost-reperfusion.

Example 8

Pulmonary vasoconstriction. The capacity of F1Cs to limit hypoxiainduced pulmonary vasoconstriction is demonstrated using an animal modelessentially as follows. Isolated perfused ferret lungs are anestablished animal model to study secondary pulmonary hypertension. Inbrief, male ferrets are anesthetized with intraperitoneal pentobarbitalsodium and the chest is opened. Stainless steel cannulae are secured inthe left atrium and pulmonary artery, and the pulmonary artery and theaorta are ligated. The lungs are perfused with a mixture of autologousblood and Krebs-Henseleit buffer in a circulating manner at a constantrate of about 85 mL/min. The perfusion circuit includes a perfusatereservoir, a roller perfusion pump, filter, and a heat exchanger. Theperfusion system is made of, e.g., tygon tubing, which is used forconnections and for passage through the perfusion pump. The temperatureof the perfusate is kept about 37-38° C. and the pH is maintained at7.35 to 7.40 by adding sodium bicarbonate to the reservoir as needed.The venous reservoir is placed below the lowermost portion of the lung.

The lungs are ventilated with a hypoxic gas mixture of 5% CO₂, 4% O₂,and 91% N₂ by a tracheotomy with a Harvard animal respirator for 30minutes. The animals are ventilated with a tidal volume of 30 mL, at arate of 18 breaths/min. and with 2 cm of H₂O positive end-expiatorypressure. For measurements, pulmonary arterial, left atrial and trachealpressures are monitored using Gould Statha P231 D pressure transducersor an equivalent connected to the inflow circulation and recorded on,e.g., a Grass polygraph. After 30 minutes of ventilation with hypoxicgas mixture, a formula 1 compound in a dose between about 5-25 mg/kgbody weight is added to the reservoir, and perfusate is allowed toperfuse the ferret lungs for 1.5 hours. Pulmonary artery pressure ismeasured until the end of the experiment, i.e., a total of two hours.Pressure that remains at or near basal level indicates the vasodilatoryeffect of the F1C in pulmonary circulation that is otherwise constrictedin response to hypoxia. The effects of the F1Cs can be compared to theeffects and duration of nitric oxide, a therapeutic agent that isoptionally used in this model as a control.

Example 9

Antiglucocorticoid effects of formula 1 compounds. A series of tests isrun in triplicate using BALB/c mouse spleen cells to demonstrate theeffect of the F1Cs and hydrocortisone (“Hycort”) on cellularproliferation in the absence of a mitogen. Cultures of spleen cells areprepared and F1Cs are added at, e.g., 0.1, 0.5, 1 and 5 μM. Suitablecontrols are used. Twenty four hours after setup, about 50 μCi[³H]-thymidine is added to each cell. Four to six hours later, the cellsare harvested and counted on a scintillation counter.

Spleen cells are obtained from normal BALB/c mice and prepared as asingle cell suspension at a concentration of about 1×10⁷ cells/ml inRPMI 1640 supplemented with 2 mM L-glutamine, 5×10⁻⁵ M2-mercaptoethanol, 20 μg/ml gentamycin-sulfate, and 1% Nutridona-NS(Boehringer-Mannheim). Individual aliquots of cells are then pulsed for30 minutes at 37° C. with selected concentrations of formula 1compounds. After pulsing, the cells are washed several times in balancedsalt solution, resuspended in fresh medium, and then dispensed into24-well culture plates with a stimulatory concentration of anti-CD3(e.g., Leo et al. Proc. Natl. Acad. Sci. U.S.A., 84:1374 (1987)). Aftera 24-hour incubation period, culture supernatants are harvested forassessment of proliferation or cytokine production, e.g., IL-2, IL-3 orIL-4 using, e.g., the method of Mossman (J. Immunol. Meth. 65:55(1983)). 100% control titers of IL-3, IL-2 or IL-4 from normalstimulated splenocytes are obtained, exemplary values may be about 640units/mL or IL-2 and 160 units/mL for IL-4.

Effects of formula 1 compounds and Hydrocortisone on Proliferation inthe Presence of a Mitogen. A series of spleen cell cultures is run usinga formula 1 compound and/or hydrocortisone with cell cultures to whichconcanavalin A is added. Preliminary tests on cultures to whichconcanavalin A is added at concentrations of 10.0, 5.0, 2.5 and 1.0ng/mL. All tests on the effects of invention compounds on culturesstimulated with concanavalin A are performed with concanavalin A at,e.g., about 2.5 ng/mL. A mitogen such as ConA generally increases cellproliferation and the glucocorticoid steroid (“GCS”) can decreaseproliferation. Detectable partial or complete reversal of the inhibitoreffects of hydrocortisone indicate an anti-glucorticoid effect by theformula 1 compounds.

Effect of formula 1 compounds on IL-3 production. Exemplary formula 1compounds are characterized for their effect on the level of thecytokine IL-3 expression by spleen cells in tissue culture and for theircapacity to reverse the effects of a GCS in IL-3 expression. The spleencell cultures are prepared in accordance with the general method above.After 30 hours the level of IL-3 in the supernatants of the cultures wasmeasured using the IL-3 ELISA kit manufactured by EndoGen Inc., Boston,Mass. A GCS such as hydrocortisone will generally suppress theproduction of IL-3 and the invention compounds are examined for theircapacity to modify this effect. The IL-3 expressed by cells in culturemay be recovered from the media containing IL-3 by known methods such assingle or sequential reverse-phase HPLC steps on a preparative HPLCcolumn. (See Urdal, et al., J. Chromatog. 296:171 (1984) and U.S. Pat.No. 5,128,450).

Example 10

Treatment of neurodegenerative conditions. Experimental allergicencephalomyelitis (EAE), is demyelinating disease of the central nervoussystem with many pathological and clinical similarities with multiplesclerosis (MS). EAE is thus a recognized animal model for humanautoimmune conditions such as MS. F1Cs such as3β,7β-dihydroxy-17β-aminoandrost-5-ene and3β-hydroxy-17β-aminoandrost-5-ene are tested for their capacity to delaythe onset of EAE or to reduce its symptoms. Female SJL mice (5 animalsper group) are immunized with 150 to 200 μg of PLP-139-151 peptide/CFAto induce EAE. Starting 7 days before injection of the peptide, theanimals are given daily injections (s.c.) of the compounds (3.0 mg) in0.1 mL vehicle, or vehicle alone for 33 days. The vehicle consisted of asuspension of the formula 1 compound in saline andcarboxymethylcellulose. Delayed onset, reduced peak clinical score (from5.2±0.6 to 2.8±1.8) and cumulative disease index (>60%) of EAE, andprevention of or significant attenuation of relapses are measured.Reduced numbers of PLP-139-151 specific T cell responses and reducednumbers of TNF-α producing cells in the CNS indicate reduced diseaseprogression or severity. Reduced production of autoimmune Th-1associated cytokines, is consistent with restoration of a more normalTh-1/Th-2 immune balance and/or with reduction of inflammation in thismodel.

The efficacy of the formula 1 compounds to treat other autoimmuneconditions can be determined by incorporating their use with suitableanimal models or assay methods, e.g., collagen-induced arthritis as amodel for human autoimmune polyarthritis (e.g., L. K. Myers et al.,Clin. Immunol. 2002, 102:185-191, A. Matejuk et al., Endocrinology 2002,143:313-319, S. Thornton et al., J. Immunol. 165:1557-1563). The effectof the compounds on markers of inflammation such as TNFα, MIP-1β, IL-13,IL-15, IL-17 or IL-18, e.g., reduced expression or activity, isoptionally observed in any autoimmune or inflammatory condition.

Example 11

Modulation of transcription. The effect of 16α-bromoepiandrosterone(“BrEA”) on transcript levels in cells in vitro was studied using amicroarray to allow simultaneous monitoring of the expression of manygenes to allow detailed analysis of the molecular pathways involved inbiological responses to the compound.

In general, microarray technology works by covalently linking short DNAsequences that are complementary to the transcripts of many differentgenes on a single slide or array chip. mRNAs from test and controlsamples are generated and labeled with one or more colored fluorescentdyes or probes. The probes are hybridized with the array, which is thenscanned by laser. The color and intensity of the fluorescent signal ateach spot denotes relative expression level of each gene. The capacityof other F1Cs described herein, e.g., a F1C in compound group 1, 2, 3, 4or 5, to modulate gene expression is characterized in a similar manner.

The array used in the experiment described below, contained about 12,000known genes. The experiment used U937 human promonocytic leukemia cellsthat differentiate to monocyte/macrophage cells in the presence ofphorbol-12-myristate-13-acetate (“PMA”). The U937 cells were PMA treatedand then exposed to BrEA for 1 hr, 2 hrs, or 4 hrs, followed bybacterial lipopolysaccharide (“LPS”) stimulation for 1 hr, 2 hrs or 4hrs. The level of transcripts of the genes on the array was measured atthe time points using RNA prepared from BrEA-treated and control (noBrEA) cells. U937 cells were plated at 1×10⁵ cells/mL in the presence of3 ng/mL PMA (Sigma, Catalog #P-8139) for 48 hrs. Cells were then treatedwith either 10 μM BrEA or DMSO (vehicle) for 1 hr, 2 hr, and 4 hrs. Ateach time point, cells were harvested and total RNA was extracted usingQiagen Rneasy kit according to manufacturer's specification. Total RNAsamples were then analyzed by Mergen Ltd. (San Leandro, Calif.www.mergen.com) to perform microarray assay.

For the microarray assay, Dnase-treated total RNA (20 micrograms) wasreverse-transcribed using an oligo[(dT)₂₄ T7 promoter]₆₅ primer(consisting of the nucleotide binding sequence for the T7 RNA polymerasefollowed by 24 thymidine nucleotides). This was followed by secondstrand synthesis. The reaction mixture was then treated with Rnase I todigest the remaining RNA. The double-stranded cDNA was phenol-chloroformextracted and used as template for in vitro transcription (T7MEGAscript, Ambion, Inc.) to generate biotin-labeled cRNA probes. Theseprobes were hybridized overnight at 30° C. with continuous agitation toMergen's ExpressChip HO5 DNA Microarray System (catalog number HO5-001)containing 12,000 genes. The arrays were then washed, and hybridizedprobes were detected using Mergen's cyanine-3 fluorescent dye-conjugatedprotein. Chips were imaged using an Affymetrix 417-418 formAffymetrix/Genetic MicroSystems (www.affymetrix.com) and spot intensitywas quantitated using ImaGene from BioDiscovery Inc.(www.biodiscovery.com).

The results showed that BrEA was capable of substantially up-regulatinga number of genes. A number of genes were differentially regulated byBrEA based on two criteria: 1) the expression level of any particulargene in a BrEA-treated sample is at least two-fold higher than that ofthe control-treated sample; and 2) the expression level of anyparticular gene in a BrEA-treated sample is significantly higher thanbackground. The up-regulation of many of these genes most apparent at 4hr after treatment, at which time roughly 700 genes were within theabove criteria. Some examples are shown in the following list. Theratios given in the list are from BrEA treated cells compared to controlcells not treated with BrEA.

Ratio* UniGene ID UniGene symbol HO5 gene description 5.3 Hs.460 ATF3Activating transcription factor 3 5.4 Hs.78546 ATP2B1 ATPase, Ca++transporting, plasma membrane 1 10.2 Hs.2128 DUSP5 Dual specificityphosphatase 5 9.7 Hs.155119 EHD1 EH-domain containing 1 9.6 Hs.75765GRO2 GRO2 oncogene 124.7 Hs.89690 GRO3 GRO3 oncogene 7.8 Hs.274402HSPA1B Heat shock 70 kD protein 1B 32.0 Hs.177781 MGC5618 Hypotheticalprotein MGC5618 6.6 Hs.75063 HIVEP2 immunodeficiency virus type Ienhancer- binding protein 2 21.5 Hs.727 INHBA Inhibin, beta A (activinA, activin AB alpha polypeptide) 53.0 Hs.81134 IL1RN Interleukin 1receptor antagonist 27.5 Hs.126256 IL1B Interleukin 1, beta 7.6 Hs.12503IL15RA Interleukin 15 receptor, alpha 131.8 Hs.98309 IL23A Interleukin23, alpha subunit p19 16.9 Hs.50640 SSI-1 JAK binding protein 7.7Hs.24684 KIAA1376 KIAA1376 protein 6.9 Hs.164719 KIAA1726 KIAA1726protein 7.1 Hs.151988 MAP3K5 Mitogen-activated protein kinase kinasekinase 5 25.5 Hs.301183 MAIL Molecule possessing ankyrin repeats inducedby lipopolysaccharide (MAIL), homolog of mouse 30.0 Hs.75607 MACSMyristoylated alanine-rich protein kinase C substrate (MARCKS, 80K-L)6.4 Hs.109281 NAF1 Nef-associated factor 1 11.3 Hs.81328 NFKBIA Nuclearfactor of kappa light polypeptide gene enhancer in B-cells inhibitor,alpha 26.1 Hs.77729 OLR1 Oxidised low density lipoprotein receptor 11348.4 Hs.2050 PTX3 Pentaxin-related gene, rapidly induced by IL-1 beta14.5 Hs.80205 PIM2 Pim-2 oncogene 9.2 Hs.239138 PBEF Pre-B-cellcolony-enhancing factor 5.4 Hs.3407 PKIG Protein kinase (cAMP-dependent,catalytic) inhibitor gamma 6.6 Hs.103755 RIPK2 Receptor-interactingserine-threonine kinase 2 29.2 Hs.183601 RGS16 Regulator of G-proteinsignalling 16 5.3 Hs.115521 REV3L REV3 (yeast homolog)-like, catalyticsubunit of DNA polymerase zeta 5.9 Hs.27018 LOC51285 Ris 8.4 Hs.82085SERPINE1 Serine (or cysteine) proteinase inhibitor, clade E (nexin,plasminogen activator inhibitor type 1), member 1 9.0 Hs.1087 STK2Serine/threonine kinase 2 5.9 Hs.167503 STAT5A Signal transducer andactivator of transcription 5A 40.4 Hs.72918 SCYA1 Small induciblecytokine A1 (I-309, homologous to mouse Tca-3) 67.3 Hs.75703 SCYA4 Smallinducible cytokine A4 (homologous to mouse Mip-1b) 174.0 Hs.75498 SCYA20Small inducible cytokine subfamily A (Cys- Cys), member 20 7.0 Hs.271387SCYA8 Small inducible cytokine subfamily A (Cys- Cys), member 8(monocyte chemotactic protein 2) 39.7 Hs.318885 SOD2 Superoxidedismutase 2, mitochondrial 17.4 Hs.112259 TRG@ T cell receptor gammalocus 15.0 Hs.2134 TRAF1 TNF receptor-associated factor 1 10.3 Hs.17839GG2-1 TNF-induced protein 17.4 Hs.101382 TNFAIP2 Tumor necrosis factor,alpha-induced protein 2 5.1 Hs.211600 TNFAIP3 Tumor necrosis factor,alpha-induced protein 3 1733.0 Hs.29352 TNFAIP6 Tumor necrosis factor,alpha-induced protein 6 *Ratio of BrEA treated cells compared to controlcells not treated with BrEA

As seen from the data shown above, BrEA was capable of inducing anincrease in the level of transcription of a number of genes. Theseincreases ranged from about a 2-fold increase to an increase of greaterthan about 1700-fold. For some genes, levels of mRNA increased from anearly undetectable level to a very high level. For genes that aremodulated by the formula 1 compounds, the level of mRNA, protein or oneor more biological activities associated with the gene product can thusinclude an increase or a decrease of at least about 3-fold, at leastabout 5-fold, at least about 10-fold, at least about 20-fold, at leastabout 50-fold or at least about 100-fold. This increase or decrease mayoccur for 1, 2, 3, 4, 5, 6 or more of the affected genes.

Pathways through which BrEA may mediate its effects include one or moreof the following. At 1 hr, transcripts of USF1, c-Fos, EGR1, and Cul1were increased. Cul1 activates NFkB1p50. At 2 hrs, USF1 increases FCARtranscript levels. At 4 hrs, c-Fos/C/EBPβ stimulate transcription ofRANTES, NFκB1p50, IL6, ICAM1, TSG (TNFAIP6), and IL1β. NFκB1p50/RelAinduces IL-2Rα, IL6, GRO2 and GRO3. At 5 hrs, USF1 increases HO1transcript levels. Alternatively, at 4 hrs, Jun B is also increased, andc-Fos/JunB & JunB/ATF3 increase c-Jun. c-Fos/c-Jun increases ATF-3,MMP1, TNFα and TSG-6 (TNFAIP3). Elevated AP1 or EGR1 increases TGFβ.ATF-3/c-Jun & c-Fos increase MMP3. Activity associated with the presenceof the NFkBp50/RelA complex increases IL-8. NFkBp50, STAT5A and STAT5Binduce IL2Rα (interleukin-2 receptor α). STAT5B Induces CDKN1A. IFNγR2induces T-bet. Other formula 1 compounds will generally affect one ormore of these pathways in a similar manner.

In general, the genes showing the greatest increases in expressionbelong to the following families: chemokines (GRO2, GRO3, SCYA1, SCYA4,SCYA20, and SCYA8), cytokines and their receptors (IL1RN, IL1B, IL15RA,and IL23A), TNFα-related/induced genes (TRAF1, GG2-1, TNFAIP2, TNFAIP3,and TNFAIP6), and members of several different signal transductionpathways (e.g. MAP3K5, STAT5A, SSI-1, RGS16, and NFκBIA). Changes in theexpression level of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more ofthese genes or other genes described herein are useful as a screeningassay or method to analyze other test compounds or other formula 1compounds. The assay can identify the relative potency of the testcompound compared to the activity of BrEA or a formula 1 compound, orthe assay can identify a distinct subset of the activities seen withBrEA or another formula 1 compound, for example.

As discussed above, BrEA was found to increase immunity in anon-inflammatory cellular context, e.g., in the absence of LPS here, butBrEA decreased inflammation when the cells were in the presence of astrong inducer of inflammation. Thus, BrEA was capable of mediating bothapparently contradictory activities by context-specific regulation ofactivities. The formula 1 compounds act differently in differenttissues, depending on the physiological condition of cells or tissues ina subject or cells or tissues in vitro. In multiple systems, both inanimals and in humans, the formula 1 compounds appear to drive immunefunction toward homeostasis. This was observed in the context of HIVwhere BrEA stimulated immune response in a condition of immunesuppression. But, in the context of autoimmunity, the formula 1compounds generally limit unwanted autoimmune responses. Depending onthe state of the target cell, genes will be regulated in a manner thatoptimizes desired immune responses while limiting unwanted immuneresponses. Responses to formula 1 compounds in resting cells (e.g. atvaccination) will be different than responses in activated cells (e.g.chronic inflammation).

Screening assays using a formula 1 compound or another compound wouldinclude any method that measures the expression level of one or more ofthese genes in the presence of a test compound as compared to theirexpression in the absence of the test compound and/or compared to theexpression seen with BrEA or another formula 1 compound. This can bedone by microarray essentially as described above, as well as by mini orcustom array on a focused list of genes (such as the list above andoptionally including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more ofthe genes disclosed herein), quantitative PCR assays such as eXpresProfiling or real-time PCR (www.altheatech.com), and Northern blotanalysis. In some cases, when a target gene product is a secretedprotein, such as SCYA1, measuring protein level in the culture media forcells in tissue culture by ELISA could also be used as a screeningassay. Also, cells for this type of analysis can be obtained from asubject who has been dosed with a formula 1 compound or another testcompound. In this case, the cells could be obtained from blood, e.g.,white blood cells, or from bone marrow, lymph tissue, spleen tissue orthymus tissue.

It will be appreciated that the methods and compositions of the instantinvention can be incorporated in the form of a variety of embodiments,some of which are disclosed herein. It will be apparent to the artisanthat other embodiments exist and do not depart from the scope of theinvention. Thus, the described embodiments are illustrative and shouldnot be construed as restrictive.

For any of the uses of formula 1 compounds described herein, e.g., inany of the examples above, the results or biological effects that areobtained using individual formula 1 compounds are optionally compared tothe results or biological effects that are obtained using a referenceformula 1 compound such as 3β,17β-dihydroxyandrost-5-ene,3β,7β,17β-trihydroxyandrost-5-ene or BrEA. A reference F1C can serve asa positive control or negative control for modulation of genetranscription or activity. Other known modulators of a gene whosebiological activity is associatiated with a symptom or clinicalcondition of interest could also be used as a reference control with orwithout a reference F1C control. Such comparisons provide guidance forusing the formula 1 compounds in the different methods or clinicalconditions. Such comparison information allows, e.g., tailoring ofdosages, dosing schedules, routes of administration or drug interactionswith other therapeutic treatments in any selected application for theF1Cs.

Example 12

The effect of F1Cs on transcript or gene product levels in cells invitro is studied in vitro using a cell type of interest, e.g., themurine macrophage cell line designated RAW264.7 (“RAW” cells). For theRAW cells, the cells are maintained in a suitable medium, e.g., RPMI1640 supplemented with 10% FBS, standard Penn/Strep antibiotic solutionand 2 mM glutamine. The T1C is dissolved in a suitable solvent, e.g.,DMSO or pyrrolidone, to generate a 10 mM stock solution. For DMSOsolutions, appropriate dilutions are made to give a F1C finalconcentration in culture media of about 1 nM to about 10 μM, with afinal DMSO content of no more than 0.1% v/v. The cells are induced withLPS at 100 ng/ml (stock solution in water, diluted in serum-free culturemedia).

In a typical protocol, on day 0 the cells are plated at a density toreach a sub-confluent state of greater than about 75% confluency on thefollowing day. For 6-well plates, about 500,000 to 700,000 cells/wellare plated. On the following day, day 1, the cells are treated with theF1C or vehicle, e.g., DMSO, with or without LPS, for selected times,e.g., 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48 hours. Afterincubation, cells are harvested with a cell scraper and total RNA isextracted to generate samples for PCR analysis. 1 mL of culture media isoptionally saved at −20° C. for future ELISA analysis to determine genetranscript levels. On day 2, cells are harvested after, e.g., 24 hr ofF1C in DMSO treatment. LPS induction is started in cells pre-treatedwith F1C in, e.g., DMSO. Exemplary treatment conditions and time pointsfor cell harvesting are as follows:

No treatment 0 hr 24 hr DMSO + LPS 1 hr 4 hr 8 hr 24 hr F1C 10 μM + LPS1 hr 4 hr 8 hr 24 hr F1C 1 μM + LPS 1 hr 4 hr 8 hr 24 hr F1C 10 nM + LPS1 hr 4 hr 8 hr 24 hr DMSO 24 hr + LPS 1 hr 4 hr 8 hr 24 hr F1C 10 μM 24hr + LPS 1 hr 4 hr 8 hr 24 hr F1C 1 μM 24 hr + LPS 1 hr 4 hr 8 hr 24 hrF1C 10 nM 24 hr + LPS 1 hr 4 hr 8 hr 24 hr

Exemplary genes of interest that can be analyzed by this or a similarprotocol include 1, 2, 3, 4, 5, 6 or more of iNOS (inducible nitricoxide synthase), eNOS (constitutive nitric oxide synthase), COX-2(cycloxygenase-2, PGE2 synthase), IκBβ, TNFα, IL-1β, IL-1Ra (interleukin1 receptor antagonist), NFκB1 (p105), NFκB2 (p49/p100), IL-6, MCP-1(monocyte chemoattractant prtein-1 or CCL2), MIP-2 (macrophageinflammatory protein-2), MMP9 (matrix metalloproteinase 9), gelatinaseB, HO-1 (heme oxygenase 1), HIF1α (hypoxia inducible factor 1, alphasubunit), GCLC (gamma glutamylcycleine synthetase catalytic (heavy)subunit or γGCS-hs), GCLM (gamma glutamylcycleine synthetase modifier(light) subunit or γGCS-Is), xCT (cystine/glutamate exchangetransporter), NQO1 (NAD(P)H: quinone oxidoreductase 1), TXNRD1(thioredoxin reduatase 1), EBBP (estrogen responsive B-box protein),CYP1A1 (cytochrome P450), CD36 (SR-B), SR-A (scavenger receptor A orMsr1), ABCA1 (ATP-binding cassette transporter A1), ABCG1 (ATP-bindingcassette transporter G1), LDLR (low-density lipoprotein receptor), NR1H3(nuclear receptor 1H3 or LXRα), NR1C3 (nuclear receptor 1C3 or PPARγ),SCD-1 (stearoyl-CoA desaturase 1) and NR4A1 (nuclear receptor 4A1 orNur77). F1C that can be characterized in this manner include the F1Cs inthe compound groups described above, e.g., one or more of16α-bromoepiandrosterone, 3β,16α-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-1,5-diene,3β-hydroxy-17β-aminoandrost-5-ene,3β,7β-dihydroxy-17β-aminoandrost-5-ene,3β-hydroxy-7-oxo-17β-aminoandrost-5-ene,3α-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-17β-aminoandrost-1,5-ene,3α-hydroxy-17β-aminoandrost-1,5-diene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene or3β-hydroxy-16α-fluoro-17β-aminoandrost-1,5-diene.

To the extent not already indicated, it will be understood by those ofordinary skill in the art that any of the various specific embodiments,compounds or compositions described herein may be modified toincorporate other appropriate features, e.g., as shown in any other ofthe specific embodiments disclosed herein or in the cited references.

1. A compound having the structure

or a salt thereof, wherein the dotted line is an optional double bond;R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; R⁴ is optionallysubstituted heterocycle; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR) or —OR^(PR) and each R^(10A), R^(10B), R^(10C) andR^(10D) is independently in the α-configuration or the β-configurationand wherein R^(PR) independently are —H or a protecting group.
 2. Thecompound of claim 1 wherein the compound has the structure


3. The compound of claim 1 wherein the compound has the structure


4. The compound of claim 2 wherein R¹ is —OH, ═O or —NH—C(O)CH₃; R² is—OH or —OCH₃; and R³ is —H, —OH, —O—C(O)CH₃ or —O—C(O)CH₂CH₃.
 5. Thecompound of claim 1 wherein R⁴ is —N-pyrrolidine, —N1-pyrazolone,—N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N1-pyridine, —N-piperidine or—N-piperazine.
 6. The compound of claim 1 wherein R⁴ is 2-pyridyl,3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. 7.The compound of claim 1 wherein R⁴ is 1-aziridyl, azetidine, pyrrole,pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole,2-isoindole, 2-isoindoline, 4-morpholine, 9-carbazole or β-carboline. 8.The compound of claim 1 wherein the compound has the structure


9. A pharmaceutical formulation comprising one or more excipients and acompound according to claim
 1. 10. A compound having the structure

or a salt thereof, wherein the dotted line is an optional double bond;R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; R⁴ is optionallysubstituted heterocycle; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR) or —OR^(PR) and each R^(10A), R^(10B), R^(10C) andR^(10D) is independently in the α-configuration or the β-configurationand wherein R^(PR) independently are —H or a protecting group.
 11. Thecompound of claim 10 wherein the compound has the structure


12. The compound of claim 11 wherein the compound has the structure


13. The compound of claim 10 wherein the compound has the structure


14. The compound of claim 11 wherein R¹ is —OH, ═O or —NH—C(O)CH₃; R² is—OH or —OCH₃; and R³ is —H, —OH, —O—C(O)CH₃ or —O—C(O)CH₂CH₃.
 15. Thecompound of claim 1 wherein R⁴ is —N-pyrrolidine, —N1-pyrazolone,—N2-pyrazolone, —N-imidazolidin-2-one, —N1-imidazole,—N1-4,5-dihydroimidazole, —N-morpholine, —N1-pyridine, —N-piperidine or—N-piperazine.
 16. The compound of claim 1 wherein R⁴ is 2-pyridyl,3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl. 17.The compound of claim 1 wherein R⁴ is 1-aziridyl, azetidine, pyrrole,pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline,3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole,2-isoindole, 2-isoindoline, 4-morpholine, 9-carbazole or β-carboline.18. A pharmaceutical formulation comprising one or more excipients and acompound according to claim
 10. 19. A compound having the structure

or a salt thereof, wherein the dotted lines are optional double bonds;R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; R⁴ is —OH, ester, ether,—NH₂, —NH—C(O)CH₃, —NH—CH₃, —N(CH₃)₂, —NHOH or optionally substitutedheterocycle; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅, —C₃H₇,optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—C(halogen)₂-, —CH(α-optionally substituted alkyl), —CH(β-optionallysubstituted alkyl), —CH(α-OH), —CH(β-OH) or —C(optionally substitutedalkyl)₂-; and R⁹ is —CH(α-OH), —CH(β-OH) or —C(optionally substitutedalkyl)₂-.
 20. The compound of claim 19 wherein the compound has thestructure


21. A pharmaceutical formulation comprising one or more excipients and acompound according to claim
 19. 22. A compound having the structure

or a salt thereof, wherein the dotted lines are optional double bonds;R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; one R⁴ is —OH, ester,ether, —NH₂, —NH—C(O)CH₃, —NH—CH₃, —N(CH₃)₂, —NHOH or optionallysubstituted heterocycle; the other R⁴ is —H, optionally substitutedalkyl, halogen, —SH or —OH; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR) or —OR^(PR) and each R^(10A), R^(10B), R^(10C) andR^(10D) is independently in the α-configuration or the β-configuration,wherein R^(PR) independently are —H or a protecting group and whereinone or two of R^(10A), R^(10B), R^(10C) and R^(10D) are not —H.
 23. Thecompound of claim 22 wherein the compound has the structure


24. A compound having the structure

or a salt thereof, wherein the dotted lines are optional double bonds;R¹ is —OH, ═O, —SH, amide, ester or ether; R² is —H, —OH, ═O, halogen,optionally substituted alkyl, ester or ether; R³ is —H, —OH, halogen,optionally substituted alkyl, ester or ether; one R⁴ is —OH, ester,ether, —NH₂, —NH—C(O)CH₃, —NH—CH₃, —N(CH₃)₂, —NHOH or optionallysubstituted heterocycle; the other R⁴ is —H, optionally substitutedalkyl, halogen, —SH or —OH; R⁵ and R⁶ independently are —H, —CH₃, —C₂H₅,—C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br or —I; R⁷ is—CH₂—, —C(halogen)₂-, —CH(α-optionally substituted alkyl),—CH(β-optionally substituted alkyl), —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; R⁹ is —CH₂—, —CH(α-OH), —CH(β-OH) or—C(optionally substituted alkyl)₂-; and R^(10A), R^(10B), R^(10C) andR^(10D) independently are —H, optionally substituted alkyl, —CH₃,halogen, —SR^(PR), —OR^(PR), α-OH, β-OH or ═O and each R^(10A), R^(10B),R^(10C) and R^(10D) is independently in the α-configuration or theβ-configuration, wherein R^(PR) independently are —H or a protectinggroup and wherein R^(10A) and R^(10C), R^(10B) and R^(10C) or R^(10C)and R^(10D) are not —H.
 25. The compound of claim 24 wherein thecompound has the structure

wherein R^(10A) and R^(10C) or R^(10C) and R^(10D) independently areα-OH, β-OH or ═O.
 26. A pharmaceutical formulation comprising one ormore excipients and a compound according to claim 24.